3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives as inhibitors of glycogen synthase kinase-3beta

ABSTRACT

This invention relates to inhibitors of glycogen synthase kinase-3β, methods of treating diseases characterized by an excess of Th2 cytokines, and to 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives of Formula (I):  
                 
 
     that are inhibitors of glycogen synthase kinase -3β, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.

CROSS REFERENCE TO RELATED APPLICATION

[0001] Pursuant to 35 U.S.C. §119(e), this application claims priorityto the filing date of the U.S. Provisional Patent Application Serial No.60/221,058 filed on Jul. 27, 2000, the disclosure of which is hereinincorporated by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention is directed to3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibitglycogen synthase kinase-3β (GSK-3β) and are therefore useful in thetreatment of mammals having disease states mediated by it. The presentinvention is also directed to pharmaceutical compositions containingthese compounds, methods for preparing them, and methods for their use,in particular methods of treatment of diseases characterized by excessTh2 cytokines and/or an excess IgE production.

[0004] 2. State of the Art

[0005] Glycogen synthase kinase (GSK) is a serine/threonine kinase forwhich two isoforms, α and β, have been identified. Glycogen synthasekinase -3β(GSK-3β) was originally identified as a protein kinase whichphosphorylated and inactivated glycogen synthase a key enzyme regulatinginsulin-stimulated glycogen synthesis ((see Embi et al., Eur. J.Biochem. 107, 519-527, (1980); Rylatt et al., Eur. J. Biochem. 107,529-537, (1980); and Vandenheede et al., J. Biol. Chem. 255,11768-11774, (1980)). Subsequently, it was discovered that GSK-3β isinhibited upon insulin activation thereby allowing the activation ofglycogen synthase. Therefore, inhibition of GSK-3β stimulatesinsulin-dependent processes and is useful in the treatment of type 2diabetes which is characterized by decreased sensitivity to insulin andan increase in blood glucose level. A number of drugs such as5-iodotubercidin®, metformin®, troglitazonem®, have been used to treatdiabetes. These drugs however have limited application becausemetformin® can cause hypoglycemia, troglitazonem® can cause severehepatoxicity and 5-iodotubercidin®, a GSK-3 inhibitor, inhibits otherserine/threonine and tyrosine kinases.

[0006] Recently, it has been discovered that GSK-3β plays a role inpathogenesis of Alzheimer's disease ((see Lovestone et al., CurrentBiology, 4, 1077-86 (1994), Brownlees et al., Neuroreport, 8, 3251-3255(1997), Takashima et al., PNAS 95, 9637-9641 (1998), and Pei et al., JNeuropathol. Exp., 56, 70-78 (1997)) and bipolar disorder (see Chen etal., J. Neurochemistry, 72, 1327-1330 (1999)). It has also beendiscovered that GSK-3β is involved in blocking of early immune responsegene activation via NF-AT and regulation of apoptosis (see Beals et al.,Science, 275, 1930-33 (1997) and Pap, M. et al. J. Biochem. 273,19929-19932, (1998)). Recently, it has also been discovered that GSK-3βis required for the NF-κB mediated survival response in the TNF-αsignalling pathway involved in the proinflammatory response to infection((Hoeflich et.al., Nature, 406, 86-90 (2000)).

[0007] Furthermore, GSK-3β is also known to regulate the degradation ofa protein (β-catenin) which controls the activity of TCF family oftranscription factors ((see., Dale,T. C., Biochem. J. 329, 209-223(1998); Clevers, H. & van de Wetering, M., Trends in Genetics 13,485-489 (1997); Staal, F. J. T. et al., International Immunology 11,317-323 (1999)). The activity of this pathway has been shown to regulatethe proliferation of colonic epithelial cells; and the biochemical dataand clinical genetics demonstrate that it regulates the development ofcolon cancer.

[0008] Accordingly, there is a need for compounds that would inhibitGSK-3β and thereby provide a means for combating diseases mediated byit. This invention fulfills this and related needs.

SUMMARY OF THE INVENTION

[0009] The present invention is directed to3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives that inhibit GSK-3βand are therefore useful in the treatment of mammals having diseasestates mediated by it such as diabetes, Alzheimer's disease, bipolardisorder, ischemia, traumatic brain injury, and immunodeficiency.

[0010] In addition, Applicants have discovered that inhibition of GSK-3βactivity reduces the level of CD4+ T-helper 2 cells (Th2) which producecytokines such as IL-4, IL-5, IL-13, and promote IgE production andeosinophil differentiation. This is an important discovery because ithas been established that Th2 specific cytokines play a key role in thepathogenesis of diseases such as allergies and asthma. Therefore, thecompounds of the present invention also provide a novel approach for thetreatment of allergies and asthma.

[0011] Accordingly, in a first aspect, this invention is directed to3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives represented byFormula (I):

[0012] wherein:

[0013] R¹ and R² independently represent hydrogen, alkyl, halo,haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino,monoalkylamino, or dialkylamino;

[0014] R³ represents hydrogen, alkyl, cycloalkyl, heteroalkyl, —COR⁷(wherein R⁷ is hydrogen or alkyl), or phenyl optionally substituted withone or two substituents independently selected from the group consistingof hydrogen, alkyl, haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro,amino, acylamino, monoalkylamino, and dialkylamino;

[0015] R⁴ and R⁵ independently represent hydrogen, alkyl, halo,haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino,monoalkylamino, or dialkylamino;

[0016] R⁶ is heteroalkyl, heterocyclyl, heterocyclylalkyl,heteroalkylsubstituted heterocyclyl, heteroalkylsubstituted cycloalkyl,hetereosubstituted cycloalkyl, —OR⁸ , —S(O)_(n)R⁸ (wherein n is 0 to 2;and R⁸ is heteroalkyl, heteroaralkyl, heterocyclyl, orheterocyclylalkyl), —NR⁹R¹⁰ (wherein R⁹ is hydrogen or alkyl and R¹⁰ isheteroalkyl, heteroaralkyl, heterosubstituted cycloalkyl, heterocyclyl,or heterocyclylalkyl), or —X-(alkylene)-Y-Z (wherein X is a covalentbond, —O—, —NH—, or —S(O)_(n1−) where n1 is 0 to 2, and Y is —O—, —NH—,or —S—, and Z is heteroalkyl or SiR¹¹R¹²R¹³ where R¹¹, R¹² and R¹³ areindependently hydrogen or alkyl), or R⁶ together with R⁴ forms amethylenedioxy or ethylenedioxy group when they are adjacent to eachother; or a pharmaceutically acceptable salt thereof.

[0017] The compounds of the present invention exhibit surprisinglyeffective activity against GSK-3β. It is contemplated that the improvedactivity is due to their enhanced bioavailability and increasedmetabolic stability.

[0018] In a second aspect, this invention is directed to a method oftreatment of a disease in a mammal treatable by administration of aGSK-3β inhibitor which method comprises administration of atherapeutically effective amount of a compound of Formula (I) or itspharmaceutically acceptable salt either alone or in combination withother pharmacologically active agents. In particular, the compounds ofthis invention are useful in treating respiratory diseases such asasthma.

[0019] In a third aspect, this invention is directed to pharmaceuticalcompositions containing a therapeutically effective amount of a compoundof Formula (I) or its pharmaceutically acceptable salt and apharmaceutically acceptable excipient.

[0020] In a fourth aspect, this invention is directed to the use ofcompounds of Formula (I) in the preparation of medicaments for use inthe treatment of diseases mediated by GSK-3β.

[0021] In a fifth aspect, this invention provides processes forpreparing compounds of Formula (I).

BRIEF DESCRIPTION OF THE DRAWINGS

[0022]FIG. 1 shows the correlation between GSK inhibition by compoundsof the invention and β-catenin levels in Jurkat T-cells.

[0023]FIG. 2A shows expression of TCF7 transcripts in mRNA from theB10.D2 cells relative to that in Balb/C T-cells.

[0024]FIG. 2B shows the induction of TCF-7 by interferon-gamma.

DETAILED DESCRIPTION OF THE INVENTION

[0025] Definitions:

[0026] Unless otherwise stated, the following terms used in thespecification and claims have the meanings given below:

[0027] “Alkyl” means a linear saturated monovalent hydrocarbon radicalof one to six carbon atoms or a branched saturated monovalenthydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl,propyl, 2-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and the like.

[0028] “Alkylene” means a linear saturated divalent hydrocarbon radicalof one to six carbon atoms or a branched saturated divalent hydrocarbonradical of three to six carbon atoms, e.g., methylene, ethylene,2,2-dimethylethylene, propylene, 2-methylpropylene, butylene, pentylene,and the like.

[0029] “Alkoxy” means a radical —OR where R is an alkyl as defined abovee.g., methoxy, ethoxy, propoxy, butoxy and the like.

[0030] “Alkylthio” means a radical —SR where R is an alkyl as definedabove e.g., methylthio, ethylthio, propylthio, butylthio, and the like.

[0031] “Acyl” means a radical —C(O)R, where R is hydrogen, alkyl,cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl wherein alkyl,cycloalkyl, cycloalkylalkyl, and phenylalkyl are as defined herein.Representative examples include, but are not limited to formyl, acetyl,cylcohexylcarbonyl, cyclohexylmethylcarbonyl, benzoyl, benzylcarbonyl,and the like.

[0032] “Acylamino” means a radical —NR′C(O)R, where R′ is hydrogen oralkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl orphenylalkyl wherein alkyl, cycloalkyl, cycloalkylalkyl, and phenylalkylare as defined herein. Representative examples include, but are notlimited to formylamino, acetylamino, cylcohexylcarbonylamino,cyclohexylmethyl-carbonylamino, benzoylamino, benzylcarbonylamino, andthe like.

[0033] “Cycloalkyl” refers to a saturated monovalent cyclic hydrocarbonradical of three to seven ring carbons e.g., cyclopropyl, cyclobutyl,cyclohexyl, 4-methylcyclohexyl, and the like.

[0034] “Cycloalkylalkyl” means a radical -R^(a)R^(b) where R^(a) is analkylene group and R^(b) is cycloalkyl group as defined herein, e.g.,cyclohexylmethyl, and the like.

[0035] “Dialkylamino” means a radical —NRR′ where R and R′ independentlyrepresent an alkyl, cycloalkyl, or cycloalkylalkyl group as definedherein. Representative examples include, but are not limited todimethylamino, methylethylamino, di(1-methylethyl)amino,(cyclohexyl)(methyl)amino, (cyclohexyl)(ethyl)amino,(cyclohexyl)(propyl)amino, (cyclohexylmethyl)(methyl)amino,(cyclohexylmethyl)(ethyl)amino, and the like.

[0036] “Halo” means fluoro, chloro, bromo, or iodo, preferably fluoroand chloro.

[0037] “Haloalkyl” means alkyl substituted with one or more same ordifferent halo atoms, e.g., —CH₂Cl, —CF₃, —CH₂CF₃, —CH₂CCl₃, and thelike.

[0038] “Heteroalkyl” means an alkyl radical as defined herein whereinone, two or three hydrogen atoms have been replaced with a substituentindependently selected from the group consisting of —OR^(a),—NR^(b)R^(c), and —S(O)_(n)R^(d) (where n is an integer from 0 to 2),with the understanding that the point of attachment of the heteroalkylradical is through a carbon atom, wherein R^(a) is hydrogen, acyl,alkyl, cycloalkyl, or cycloalkylalkyl; R^(b) and R^(c) are independentlyof each other hydrogen, acyl, alkyl, cycloalkyl, or cycloalkylalkyl; andwhen n is 0, R^(d) is hydrogen, alkyl, cycloalkyl, or cycloalkylalkyl,and when n is 1 or 2, R^(d) is alkyl, cycloalkyl, cycloalkylalkyl,amino, acylamino, monoalkylamino, or dialkylamino. Representativeexamples include, but are not limited to, 2-hydroxyethyl,3-hydroxypropyl, 2-hydroxy-1-hydroxymethylethyl, 2,3-dihydroxypropyl,1-hydroxymethylethyl, 3-hydroxybutyl, 2,3-dihydroxybutyl,2-hydroxy-1-methylpropyl, 2-aminoethyl, 3-aminopropyl,2-methylsulfonylethyl, aminosulfonylmethyl, aminosulfonylethyl,aminosulfonylpropyl, methylaminosulfonylmethyl,methylaminosulfonylethyl, methylaminosulfonylpropyl, and the like.

[0039] “Hydroxyalkyl” means an alkyl radical as defined herein,substituted with one or more, preferably one, two or three hydroxygroups, provided that the same carbon atom does not carry more than onehydroxy group. Representative examples include, but are not limited to,2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl,1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl,4-hydroxybutyl, 2,3-dihydroxypropyl, 2-hydroxy-1-hydroxymethylethyl,2,3-dihydroxybutyl, 3,4-dihydroxybutyl and2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl,2,3-dihydroxypropyl and 1-(hydroxymethyl)-2-hydroxyethyl. Accordingly,as used herein, the term “hydroxyalkyl” is used to define a subset ofheteroalkyl groups.

[0040] “Heterosubstituted cycloalkyl” means a cycloalkyl radical asdefined herein wherein one, two or three hydrogen atoms in thecycloalkyl radical have been replaced with a substituent independentlyselected from the group consisting of hydroxy, alkoxy, amino, acylamino,monoalkylamino, dialkylamino, or —S(O)_(n)R (where n is an integer from0 to 2) such that when n is 0, R is hydrogen, alkyl, cycloalkyl, orcycloalkylalkyl, and when n is 1 or 2, R is alkyl, cycloalkyl,cycloalkylalkyl, amino, acylamino, monoalkylamino, or dialkylanmino.Representative examples include, but are not limited to, 2-, 3-, or4-hydroxycyclohexyl, 2-, 3-, or 4-aminocyclohexyl, 2-, 3-, or4-sulfonamidocyclohexyl, and the like, preferably 4-hydroxycyclohexyl,2-aminocyclohexyl, 4-sulfonamidocyclohexyl.

[0041] “Heteroalkylsubsituted cycloalkyl” means a cycloalkyl radical asdefined herein wherein one, two or three hydrogen atoms in thecycloalkyl radical have been replaced with a heteroalkyl group with theunderstanding that the heteroalkyl radical is attached to the cycloalkylradical via a carbon-carbon bond.. Representative examples include, butare not limited to, 1-hydroxymethylcyclopentyl,2-hydroxymethylcyclohexyl, and the like.

[0042] “Heteroaryl” means a monovalent monocyclic or bicyclic radical of5 to 12 ring atoms having at least one aromatic ring containing one,two, or three ring heteroatoms selected from N, O, or S, the remainingring atoms being C, with the understanding that the attachment point ofthe heteroaryl radical will be on an aromatic ring. The heteroaryl ringis optionally substituted independently with one or more substituents,preferably one or two substituents, selected from alkyl, haloalkyl,heteroalkyl, hydroxy, alkoxy, halo, nitro, cyano, More specifically theterm heteroaryl includes, but is not limited to, pyridyl, furanyl,thienyl, thiazolyl, isothiazolyl, triazolyl, imidazolyl, isoxazolyl,pyrrolyl, pyrazolyl, pyrimidinyl, benzofuranyl, tetrahydrobenzofuranyl,isobenzofuranyl, benzothiazolyl, benzoisothiazolyl, benzotriazolyl,indolyl, isoindolyl, benzoxazolyl, quinolyl, tetrahydroquinolinyl,isoquinolyl, benzimidazolyl, benzisoxazolyl or benzothienyl, and thederivatives thereof.

[0043] “Heteroaralkyl” means a radical -R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a heteroaryl group as defined herein, e.g.,pyridin-3-ylmethyl, imidazolylethyl, pyridinylethyl, 3-(benzofuran-2-yl)propyl, and the like.

[0044] “Heterocyclyl” means a saturated cyclic radical of 5 to 8 ringatoms in which one or two ring atoms are heteroatoms selected from NR(where R is independently hydrogen, alkyl, or heteroalkyl), 0, orS(O)_(n) (where n is an integer from 0 to 2), the remaining ring atomsbeing C, where one or two C atoms may optionally be replaced by acarbonyl group. The heterocyclyl ring may be optionally substitutedindependently with one, two, or three substituents selected from alkyl,haloalkyl, heteroalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino,monoalkylamino, dialkylamino, —COR (where R is alkyl). More specificallythe term heterocyclyl includes, but is not limited to,tetrahydropyranyl, 2,2-dimethyl-1,3-dioxolane, piperidino,N-methylpiperidin-3-yl, piperazino, N-methylpyrrolidin-3-yl,3-pyrrolidino, morpholino, thiomorpholino, thiomorpholino-1-oxide,thiomorpholino-1,1-dioxide, pyrrolinyl, imidazolinyl, and thederivatives thereof.

[0045] “Heteroalkylsubsituted heterocyclyl” means a heterocyclyl radicalas defined herein wherein one, two or three hydrogen atoms in theheterocyclyl radical have been replaced with a heteroalkyl group withthe understanding that the heteroalkyl radical is attached to theheterocyclyl radical via a carbon-carbon bond. Representative examplesinclude, but are not limited to, 4-hydroxymethylpiperidin-1-yl,4-hydroxymethylpiperazin-1-yl, 4-hydroxyethylpiperidin-1-yl,4-hydroxyethylpiperazin-1-yl, and the like.

[0046] “Heterocyclylalkyl”, “cycloalkylalkyl”, or “phenylalkyl” means aradical -R^(a)R^(b) where R^(a) is an alkylene group and R^(b) is phenylor a heterocyclyl or cycloalkyl group as defined herein, e.g.,tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl,3-piperidinylmethyl, 2,2-dimethyl-1,3-dioxoxolan -4-ylmethyl, benzyl,cyclohexylmethyl, and the like.

[0047] “Monoalkylamino” means a radical —NHR where R is an alkyl,cycloalkyl, or cycloalkylalkyl group as defined above, e.g.,methylamino, (1-methylethyl)amino, cyclohexylamino,cyclohexylmethylamino, cyclohexylethylamino, and the like.

[0048] “Optional” or “optionally” means that the subsequently describedevent or circumstance may but need not occur, and that the descriptionincludes instances where the event or circumstance occurs and instancesin which it does not. For example, “heterocyclo group optionally mono-or di-substituted with an alkyl group” means that the alkyl may but neednot be present, and the description includes situations where theheterocyclo group is mono- or di-substituted with an alkyl group andsituations where the heterocyclo group is not substituted with the alkylgroup.

[0049] “Phenylalkyl” means a radical -R^(a)R^(b) where R^(a) is analkylene group and R^(b) is a phenyl group as defined herein, e.g.,benzyl and the like.

[0050] “Hydroxy or amino protecting group” refers to those organicgroups intended to protect oxygen and nitrogen atoms against undesirablereactions during synthetic procedures . Suitable oxygen and nitrogenprotecting groups are well known in the art e.g., trimethylsilyl,dimethyl-tert-butylsilyl, benzyl, benzyloxy-carbonyl (CBZ),tert-butoxycarbonyl (Boc), trifluoroacetyl,2-trimethylsilylethanesulfonyl (SES), and the like. Others can be foundin the book by T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Second Edition, Wiley, N.Y., 1991, and references citedtherein..

[0051] Compounds that have the same molecular formula but differ in thenature or sequence of bonding of their atoms or the arrangement of theiratoms in space are termed “isomers”. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereomers” and those that are non-superimposable mirror images ofeach other are termed “enantiomers”. When a compound has an asymmetriccenter, for example, it is bonded to four different groups, a pair ofenantiomers is possible. An enantiomer can be characterized by theabsolute configuration of its asymmetric center and is described by theR- and S-sequencing rules of Cahn and Prelog, or by the manner in whichthe molecule rotates the plane of polarized light and designated asdextrorotatory or levorotatory (i.e., as (+) or (−)-isomersrespectively). A chiral compound can exist as either individualenantiomer or as a mixture thereof. A mixture containing equalproportions of the enantiomers is called a “racemic mixture”.

[0052] The compounds of this invention may possess one or moreasymmetric centers; such compounds can therefore be produced asindividual (R)- or (S)- stereoisomers or as mixtures thereof. Forexample, if the R⁶ substituent in a compound of formula (I) is2-hydroxyethyl, then the carbon to which the hydroxy group is attachedis an asymmetric center and therefore the compound of Formula (I) canexist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, thedescription or naming of a particular compound in the specification andclaims is intended to include both individual enantiomers and mixtures,racemic or otherwise, thereof. The methods for the determination ofstereochemistry and the separation of stereoisomers are well-known inthe art (see discussion in Chapter 4 of “Advanced Organic Chemistry”,4th edition J. March, John Wiley and Sons, New York, 1992).

[0053] A “pharmaceutically acceptable excipient” means an excipient thatis useful in preparing a pharmaceutical composition that is generallysafe, non-toxic and neither biologically nor otherwise undesirable, andincludes an excipient that is acceptable for veterinary use as well ashuman pharmaceutical use. A “pharmaceutically acceptable excipient” asused in the specification and claims includes both one and more than onesuch excipient.

[0054] A “pharmaceutically acceptable salt” of a compound means a saltthat is pharmaceutically acceptable and that possesses the desiredpharmacological activity of the parent compound. Such salts include:

[0055] (1) acid addition salts, formed with inorganic acids such ashydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like; or formed with organic acids such asacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid,glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid,malic acid, maleic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelicacid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonicacid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, 3-phenylpropionic acid,trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid,gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid,stearic acid, muconic acid, and the like; or

[0056] (2) salts formed when an acidic proton present in the parentcompound either is replaced by a metal ion, e.g., an alkali metal ion,an alkaline earth ion, or an aluminum ion; or coordinates with anorganic base such as ethanolamine, diethanolamine, triethanolamine,tromethamine, N-methylglucamine, and the like.

[0057] A compound of Formula (I) may act as a pro-drug. Prodrug meansany compound which releases an active parent drug according to Formula(I) in vivo when such prodrug is administered to a mammalian subject.Prodrugs of a compound of Formula (I) are prepared by modifyingfunctional groups present in the compound of Formula (I) in such a waythat the modifications may be cleaved in vivo to release the parentcompound. Prodrugs include compounds of Formula (I) wherein a hydroxy,amino, or sulfhydryl group in compound (I) is bonded to any group thatmay be cleaved in vivo to regenerate the free hydroxyl, amino, orsulfhydryl group, respectively. Examples of prodrugs include, but arenot limited to esters (e.g., acetate, formate, and benzoatederivatives), carbamates (e.g., N,N-dimethylamino-carbonyl) of hydroxyfunctional groups in compounds of Formula (I), and the like.

[0058] “Treating” or “treatment” of a disease includes:

[0059] (1) preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease,

[0060] (2) inhibiting the disease, i.e., arresting or reducing thedevelopment of the disease or its clinical symptoms, or

[0061] (3) relieving the disease, i.e., causing regression of thedisease or its clinical symptoms.

[0062] A “therapeutically effective amount” means the amount of acompound that, when administered to a mammal for treating a disease, issufficient to effect such treatment for the disease. The“therapeutically effective amount” will vary depending on the compound,the disease and its severity and the age, weight, etc., of the mammal tobe treated.

Nomenclature

[0063] The naming and numbering of the compounds of this invention isillustrated below.

[0064] The nomenclature used in this application is generally based onthe IUPAC recommendations. Since strict adherence to theserecommendations would result in the names changing substantially whenonly a single substituent is changes, compounds have been named in aform that maintains

[0065] consistency of nomenclature for the basic structure of themolecule. For example, a compound of Formula (I) where R¹, R², R⁴ and R⁵are hydrogen, R³ is methyl, R⁶ is 2-hydroxyethylamino and is meta to thecarbon attaching the phenyl ring to the pyrrole-2,5-dione ring is named3-(1-methylindolyl)-4-[3-(2-hydroxyethylaminophenyl)-1H-pyrrole-2,5-dione.

[0066] a compound of Formula (I) where R¹, R², R⁴ and R⁵ are hydrogen,R³ is methyl, R⁶ is 2-hydroxyethylamino and is para to the carbonattaching the phenyl ring to the pyrrole-2,5-dione ring is named3-(1-methylindolyl)-4-[4-(2-hydroxyethylaminophenyl)-1H-pyrrole-2,5-dione.

[0067] Reresentative compounds of this invention are as follows

[0068] I. Compounds of Formula (I) where R¹, R², R⁴ and R⁵=hydrogen,R³=methyl, and R⁶ is as defined below are:

Cpd.# R⁶ M. pt ° C. Mass Spec. Example I-1 2,3-dihydroxypropoxy  245-247.1 392 M⁺ 1 I-2 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy220.8-221.2 432 M⁺ 2

[0069] II. Compounds of Formula (I) where R¹, R², R⁴ and R⁵=hydrogen,R³=methyl, and R⁶ is as defined below are:

Cpd.# R⁶ M. pt ° C. Mass Spec. Example II-1 2-aminoethyloxyhydrochloride 182.4-187 362 M⁺  6 II-2 3-aminopropyloxy hydrochloride375 M⁺  5 II-3 2(R),3-dihydroxypropoxy 177.7-178 392 M⁺  2 II-42-morpholin-4-ylethyloxy 197.7-199 431 M⁺  3 II-52(S),3-dihydroxy-propoxy 176.9-178.1 392 M⁺  2 II-6(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy 432 M⁺  1 II-7(S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy 186.8-187.4 432 M⁺  1 II-8(RS)-2,2-dimethyl-1,3-dioxolan-4-yl- 431 M⁺  7 methylamino II-92,3-dihydroxy-propylamino 160-163.5 392 (M + H)⁺  7 II-102,2-dimethyl-1,3-dioxan-5-ylamino 201-203 431 M⁺  9 II-11(RS)-2-hydroxy-1-hydroxymethylethylamino 97.5-101 391 M⁺ 10 II-12(RS)-3-hydroxybutylamino 389 M⁺ 14 II-13 (RS)-2-hydroxy-1-methylpropylamino 389 M⁺ 15 II-13A tetrahydropyran-4-ylamino 401 M⁺  8 II-14imidazol-2-ylmethylamino 397 M⁺ 11 II-15 morpholin-4-yl hydrochloride205.3-212.6 388 M⁺  4 II-16 3-(tert-butyl-dimethylsilyl-oxy)propylamino58-65 490 (M + H)⁺ 12 II-17 2-(tert-butyl-diphenylsilyl-oxy)ethylamino600 (M + H)⁺ 12 II-18 3-hydroxypropylamino hydrochloride 180-192 376(M + H)⁺ 13 II-19 2-hydroxyethylamino hydrochloride 170.3-170.6 362 (M +H)⁺ 13 II-20 3-hydroxypropyloxy 150.2-152.6 377 (M + H)⁺ 13 II-213-(tert-butyl-dimethylsilyl-oxy)propyloxy 151.2-151.7 491 (M + H)⁺  6II-22 (RS)-1-hydroxymethylethyl-amino 203.1-205.8 376 (M + H)⁺ 15 II-233-hydroxy-1-methylpropylamino 389 M⁺ 14 II-24(RS)-bis(2,3-dihydroxy-propyl)amino 466 (M + H)⁺  7 II-25pyrrolidin-1-yl 372 M⁺  4 II-26 (S)-2-hydroxy-2-hydroxymethylethylamino392 (M + H)⁺  7 II-27 2(R),3-dihydroxy-propylamino.HCl 392 (M + H)⁺  7II-28 4-hydroxycyclohexylamino 415 M⁺  8 II-29 4-hydroxypiperidin-1-yl136.0-141.0 402 (M + H)⁺ 23 II-30 (R)-2,2-dimethyl-1,3-dioxolan-4-yl-448 M⁺ 18 methylsulfanyl II-31 (R)-2,3-dihydroxypropylsulfanyl 408 M⁺ 21II-32 (R)-2,2-dimethyl-1,3-dioxolan-4-yl- 465 (M + H)⁺ 19 methylsulfinylII-33 (R)-2,3-dihydroxypropylsulfinyl 425 (M + H)⁺ 21 II-34(R)-2,2-dimethyl-1,3-dioxolan-4-yl- 481 (M + H)⁺ 20 methylsulfonyl II-35(R)-2,3-dihydroxypropylsulfonyl 411 (M + H)⁺ 21

[0070] III. Compounds of Formula (I) where R², R⁴ and R⁵=hydrogen, R¹,R³ and R⁶ are as defined below are:

Cpd. Mass # R¹ R³ R⁶ M. pt ° C. Spec. Example III-1 Chloro methyl(RS)-2,3-dihydroxypropylamino 224.5-225.7 426 16 (M + H)⁺ III-2 fluoromethyl 3-aminopropyloxy hydrochloride 223.2-225.0 410 17 (M + H)⁺ III-3H H 2-(morpholin-4-yl)-ethoxy 417  3 (M + H)⁺ III-4 chloro methyl((R)-2-hydroxy-2- 427 24 hydroxymethyl)ethyloxy (M + H)⁺ III-5 fluoromethyl ((R)-2-hydroxy-2- 411 24 hydroxymethyl)ethyloxy (M + H)⁺ III-6fluoro 3- (RS)-2,3-dihydroxy- 454 22 hydrox propylamino (M + H)⁺ y-propyl III-7 methoxy methyl 2,3-dihydroxy-propylamino 421 25 III-8methyl methyl 2,3-dihydroxy-propylamino 405 25 III-9 isopropo methyl2,3-dihydroxy-propylamino 449 26 xy

[0071] IV. Compounds of Formula (I) where R¹, R², R⁴ and R⁵=hydrogen,R³=methyl, and R⁶ is as defined below are:

Cpd. # R⁶ m. pt ° C. Mass Spec. Example IV-1(R)-2,2-dimethyl-1,3-dioxolan-4-y1- 432 M⁺ 1 methyloxy IV-2(RS)-2,3-dihydroxy-propylamino 212-213.5 7 IV-3(RS)-2,2-dimethyl-1,3-dioxolan-4-yl- 85-87.8 7 methylamino IV-43-hydroxybutylamino 58-61.5 389 M⁺ 13  IV-5(RS)-1-methyl-2-hydroxyethylamino 375 15  IV-6 2(R),3-dihydroxypropoxy220.3-222.7 392 M⁺ 1

[0072] V. Additional compounds of Formula (I) where only one of R⁴-R⁶ ishydrogen are:

[0073]3-(1-methyl-indol-3-yl)-4-{3-((R)-2,3-dihydroxy-propoxyl)-2-methylphenyl}-1H-pyrrole-2,5-dione (Example 27); and

[0074]3-(1-methyl-indol-3-yl)-4-{3-((R)-2,3-dihydroxy-propoxyl)-2-nitrophenyl}-1H-pyrrole-2,5-dione(Example 28).

[0075]3-(1-methylindol-3-yl)-4-[5-((R)-2,3-dihydroxypropoxy)-2-nitrophenyl]-1H-pyrrole-2,5-dione(Example 28).

PREFERRED EMBODIMENTS

[0076] While the broadest definition of this invention is set forth inthe Summary of the Invention, certain compounds of Formula (I) arepreferred.

[0077] (A) A preferred group of compounds is that wherein R³ is alkyl,preferably methyl or ethyl, more preferably methyl.

[0078] Within this group a more preferred group of compounds is thatwherein R⁶ group is at the 3- or 5-position of the phenyl ring,preferably R⁶ is at the 3- position of the phenyl ring.

[0079] Within this group a more preferred group of compounds is thatwherein R⁶ is heteroalkyl.

[0080] Another more preferred group of compounds is that wherein R⁶ isheterocyclylalkyl.

[0081] Yet another more preferred group of compounds is that wherein R⁶is —OR⁸ (wherein R⁸ is heteroalkyl or heterocyclylalkyl), preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethyloxy, 3-hydroxypropyloxy,2-aminoethyloxy, 3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (R) or(S) 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy, more preferably (RS), (R)or (S) 2-hydroxy-2-hydroxymethylethyloxy.

[0082] Yet another more preferred group of compounds is that wherein R⁶is —NHR¹⁰ (wherein R¹⁰ is heteroalkyl, heterocyclyl, orheterocyclylalkyl), preferably (RS), (R) or (S)2-hydroxy-2-hydroxymethylethylamino, 2-hydroxyethylarnino,3-hydroxypropylarnino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 2,2-dimethyl-1,3-dioxan-5-ylamino,2-hydroxy-1-hydroxymethylethylamino, 3-hydroxybutylamino,imidazol-2-ylmethylamino, or tetrahydropyran-4-ylamino, more preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethylamino, (RS), (R) or (S)2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 3-hydroxybutylamino, or2-hydroxy-1-hydroxymethyl-ethylamino.

[0083] Yet another more preferred group of compounds is that wherein R⁶heterocyclyl or -X-(alkylene) —Y—heteroalkyl (wherein X is a covalentbond, —O— or —NH— and Y is —O— or —NH-), preferably heterocyclyl, morepreferably morpholin-4-yl or pyrrolidin-1-yl.

[0084] Within these preferred and more preferred groups of compounds, aneven more preferred group of compounds is that wherein:

[0085] R¹ and R² are hydrogen; or R¹ is halo, preferably chloro and islocated at the 5-position of the indole ring and R² is hydrogen; and

[0086] R⁴ and R⁵ are at the 2- and the 6- positions of the phenyl ringrespectively and are hydrogen, alkyl, halo, alkoxy, cyano or nitro,preferably hydrogen, chloro or fluoro, more preferably R⁴ and R⁵ areboth hydrogen or one of R⁴ and R⁵ is fluoro and the other is hydrogen,or both of R⁴ and R⁵ are fluoro.

[0087] (B) Another preferred group of compounds is that wherein R⁶ groupis at the 3- or 5-position of the phenyl ring, preferably R⁶ is at the3- position of the phenyl ring.

[0088] Within this group a more preferred group of compounds is thatwherein R⁶ is heteroalkyl.

[0089] Another more preferred group of compounds is that wherein R⁶ isheterocyclylalkyl.

[0090] Yet another more preferred group of compounds is that wherein R⁶is—OR⁸ (wherein R⁸ is heteroalkyl or heterocyclylalkyl), preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethyloxy, 3-hydroxypropyloxy,2-aminoethyloxy, 3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (R) or(S) 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy, more preferably (RS), (R)or (S) 2-hydroxy-2-hydroxymethylethyloxy.

[0091] Yet another more preferred group of compounds is that wherein R⁶is —NHR¹⁰ (wherein R¹⁰ is heteroalkyl, heterocyclyl, orheterocyclylalkyl), preferably (RS), (R) or (S)2-hydroxy-2-hydroxymethylethylamino, 2-hydroxyethylamino,3-hydroxypropylamino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 2,2-dimethyl-1,3-dioxan-5-ylamino,2-hydroxy-1-hydroxymethylethylamino, 3-hydroxybutylamino,irnidazol-2-ylmethylamino, or tetrahydropyran-4-ylamino, more preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethylamino, (RS), (R) or (S)2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 3-hydroxybutylamino, or2-hydroxy-1-hydroxymethylethylamino.

[0092] Yet another more preferred group of compounds is that wherein R⁶heterocyclyl or -X-(alkylene) -Y-heteroalkyl (wherein X is a covalentbond, —O— or —NH— and Y is —O— or —NH), preferably heterocyclyl, morepreferably morpholin4-yl or pyrrolidin-1-yl.

[0093] Within these preferred and more preferred groups of compounds, aneven more preferred group of compounds is that wherein R³ is alkyl,preferably ethyl or methyl, more preferably methyl.

[0094] Within these preferred, more preferred, and even more preferredgroups of compounds, a particularly preferred group of compounds is thatwherein:

[0095] R¹ and R² are hydrogen; or R¹ is halo, preferably chloro and islocated at the 5-position of the indole ring and R² is hydrogen; and

[0096] R⁴ and R⁵ are at the 2- and the 6- positions of the phenyl ringrespectively and are hydrogen,alkyl, halo, alkoxy, cyano or nitro,preferably hydrogen, chloro or fluoro, more preferably R⁴ and R⁵ areboth hydrogen, or one of R⁴ and R⁵ is fluoro and the other is hydrogen,or both of R⁴ and R⁵ are fluoro.

[0097] (C) Yet another preferred group of compounds is that wherein R¹and R² groups are at the 5- and 7-positions of the indole ringrespectively; R⁴ an R⁵ groups are at the 2- and the 6-positions of thephenyl ring respectively and the R⁶ group is at the 3- or 5-position ofthe phenyl ring, preferably R⁶ is at the 3- position of the phenyl ring.

[0098] Within this group a more preferred group of compounds is thatwherein R⁶ is heteroalkyl.

[0099] Another more preferred group of compounds is that wherein R⁶ isheterocyclylalkyl.

[0100] Yet another more preferred group of compounds is that wherein R⁶is —OR⁸ (wherein R⁸ is heteroalkyl or heterocyclylalkyl), preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethyloxy, 3-hydroxypropyloxy,2-aminoethyloxy, 3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (R) or(S) 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy, more preferably (RS), (R)or (S) 2-hydroxy-2-hydroxymethylethyloxy.

[0101] Yet another more preferred group of compounds is that wherein R⁶is —NHR¹⁰ (wherein R¹⁰ is heteroalkyl, heterocyclyl, orheterocyclylalkyl), preferably (RS), (R) or (S)2-hydroxy-2-hydroxymethylethylamino, 2-hydroxyethylamino,3-hydroxypropylamino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylarnino, 2,2-dimethyl- 1,3-dioxan-5-ylamino,2-hydroxy- 1-hydroxymethylethylamino, 3-hydroxybutylamino,imidazol-2-ylmethylamino, or tetrahydropyran-4-ylamino, more preferably(RS), (R) or (S) 2-hydroxy-2-hydroxymethylethylamino, (RS), (R) or (S)2,2-dimethyl- 1,3-dioxolan-4-ylmethylamino, 3-hydroxybutylamino, or2-hydroxy-1 -hydroxymethyl-ethylamino.

[0102] Yet another more preferred group of compounds is that wherein R⁶heterocyclyl or -X-(alkylene) —Y—heteroalkyl (wherein X is a covalentbond, —O— or —NH— and Y is —O— or —NH), preferably heterocyclyl, morepreferably morpholin-4-yl or pyrrolidin-1-yl.

[0103] Within these preferred and more preferred groups of compounds, aneven more preferred group of compounds is that wherein R³ is alkyl,preferably ethyl or methyl, more preferably methyl

[0104] Within these preferred, more preferred, and even more preferredgroups of compounds, a particularly preferred group of compounds is thatwherein:

[0105] R¹ and R² are hydrogen; or R¹ is halo, preferably chloro and R²is hydrogen; and

[0106] R⁴ and R⁵ are hydrogen, alkyl, halo, alkoxy, cyano or nitro,preferably hydrogen, chloro or fluoro, more preferably R⁴ and R⁵ areboth hydrogen or one of R⁴ and R⁵ is fluoro and the other is hydrogen,or both of R⁴ and R⁵ are fluoro.

GENERAL SYNTHETIC SCHEME

[0107] Compounds of this invention can be made by the methods depictedin the reaction schemes shown below.

[0108] The starting materials and reagents used in preparing thesecompounds are either available from commercial suppliers such as AldrichChemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA),Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methodsknown to those skilled in the art following procedures set forth inreferences such as Fieser and Fieser's Reagents for Organic Synthesis,Volumes 1-15 (John Wiley and Sons, 1991); Rodd's Chemistry of CarbonCompounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers,1989), Organic Reactions, Volumes 140 (John Wiley and Sons, 1991),March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition),and Larock's Comprehensive Organic Transformations (VCH Publishers Inc.,1989). These schemes are merely illustrative of some methods by whichthe compounds of this invention can be synthesized, and variousmodifications to these schemes can be made and will be suggested to oneskilled in the art having referred to this disclosure. (make surelastest volumes included, any better book and suppliers of sm)

[0109] The starting materials and the intermediates of the reaction maybe isolated and purified if desired using conventional techniques,including but not limited to filtration, distillation, crystallization,chromatography, and the like. Such materials may be characterized usingconventional means, including physical constants and spectral data.

[0110] Preparation of compounds of Formula (I)

[0111] Schemes 1-4 describe alternative methods to prepare the compoundsof Formula (I).

[0112] Compounds of Formula (I) where R³ is methyl, R⁶ is —NHR¹⁰, andother groups are as defined in the Summary of the Invention can beprepared as shown in Scheme 1 below.

[0113] Acylation of N-methylindole of formula 1 with oxalyl chloride inan ethereal solvent such as diethyl ether provides a indole-3-glyoxylylchloride of formula 2. The reaction is typically carried out between 0°C. and room temperature, preferably at 0°C. Compounds of formula 1 arecommercially available or they can be prepared by methods well known inthe art. For example, 1-methylindole, 4-methoxy-1-methylindole, and5-bromo-1-methylindole are commercially available.5-chloro-1-methylindole can be prepared by alkylation of commerciallyavailable 5-chloroindole by methods well known in the art such astreating 5-chloroindole with alkylhalide in the presence of a base suchas sodium hydride in solvents such as dimethylformamide. Similarly,various other substituted indoles such as 5-fluoroindole and 4-, 5-, 6-,or 7-dimethylindole that are also commercially available and can beconverted to the N-alkylindoles by alkylation as described above.

[0114] Condensation of 2 with a nitrophenylacetic acid of formula 3provides 3-indolino-4-(nitrophenyl) -2,5-furandione of formula 4. Thereaction is carried out in an inert organic solvent such as methylenechloride, chloroform, and the like and in the presence of anon-nucleophilic organic base such as triethylamine, diisopropylamine,and the like. Nitrophenylacetic acids of formula 3 are commerciallyavailable. For example 2-, 3-, and 4-nitrophenylacetic acids arecommercially available from Aldrich. Other nitrophenyl acetic acids maybe prepared from the corresponding cyano-halobenzenes by homologation ofthe cyano group to an acetic acid side chain by methods well known inthe art. For example, 2,6-difluoro-3-nitrocyanobenzene can be convertedto 2,6-difluoro-3-nitrophenylacetic acid as follows. Hydrolysis of thecyano group in 2,6-difluoro-3-nitrocyanobenzene under acidic hydrolysisreaction conditions provides 2,6-difluoro-3-nitrobenzoic acid which isthen treated with a chlorinating agent such as oxalyl chloride toprovide 2,6-difluoro-3-nitrobenzoyl chloride. Treatment of2,6-difluoro-3-nitrobenzoyl chloride with diazomethane provides thecorresponding diazoketone derivative which upon treatment with silversalt of benzoic acid (see Fieser Vol. I, pg. 1004) in the presence oftriethylamine in methanol provides methyl 2,6-difluoro-3-nitrophenylacetate. Hydrolysis of methyl2,6-difluoro-3-nitrophenylacetate under basic hydrolysis reactionconditions (e.g., lithium hydroxide in aqueous methanol) provides thedesired 2,6-difluoro -3-nitrophenylacetic acid.

[0115] Treatment of 4 with aqueous ammonium hydroxide in a high boilingorganic solvent such as N,N-dimethylformamide provides3-indolino-4-(nitrophenyl)-1H-pyrrole-2,5-dione of formula 5. Thereaction is typically carried out between 130-140° C.

[0116] Reduction of the nitro group in 5 with a suitable reducing agentsuch as titanium trichloride in acetone provides a compound of formula 6which is then converted to a compound of Formula (I) wherein R⁶ is agroup of formula —NHR¹⁰ wherein R¹⁰ is as defined in the Summary of theInvention by methods well known in the art. For example, a compound ifFormula (I) where R¹⁰ is a heteroaralkyl, heterocyclic, orheterocyclylalkyl group such as 2-imidazolylmethyl,2,2-dimethyl-1,3-dioxan -5-yl, or 2,2-dimethyldioxolan-4-ylmethyl can beprepared by reacting a compound of formula 6 with2-imidazole-carboxyaldehyde, 2,2-dimethyl- 1,3-dioxan-5-one, and2,2-dimethyldioxolan4-carboxyaldehyde respectively, under reductiveamination reaction conditions i.e., carrying out the reaction in thepresence of a suitable reducing agent (e.g., sodium cyanoborohydride,sodium triacetoxyborohydride, and the like) and an organic acid (e.g.,glacial acetic acid, trifluoroacetic acid, and the like) at ambienttemperature. Suitable solvents for the reaction are halogenatedhydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like).2,2-Aldehydes and ketones such as 2-imidazolecarboxyaldehyde,2,2-dimethyl-1,3-dioxan-5-one, and2,2-dimethyldioxolan-4-carboxyaldehyde are commercially available.2,2-Dimethyldioxolane-4-carboxyaldehyde can be prepared by the proceduredescribed in Dumont, von R., et al., Helv. Chim. Acta, 66, 814, (1983).

[0117] As will be apparent to a person skilled in the art, a compound ofFormula (I) can be converted to other compounds of Formula (I). Forexample, acidic hydrolysis of compound (I) wherein R¹⁰ is2,2-dimethyldioxolan-4-ylmethyl provides a compound of Formula (I)wherein R¹⁰ is a 2,3-dihydroxy-propyl dihydroxy-propyl group.

[0118] Compounds of Formula (I) where R³ is methyl, R⁶ is heteroalkyl,heterocyclyl or —OR⁸ wherein R⁸ is heteroalkyl, heteroaralkyl,heterocyclyl, or heterocyclylalkyl, and other groups are as defined inthe Summary of the Invention can be prepared as shown in Scheme 2 below.

[0119] Reaction of a compound of formula 2 with a compound of formula 7(where R⁶ is heteroalkyl, heterocyclyl, or —OR⁸ wherein R⁸ isheteroalkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl) underthe reaction conditions described in Scheme 1 above provides a3-indolino-4-phenyl-2,5-furandione of formula 8.

[0120] Compounds of formula 7 where R⁶ is heteroalkyl, heterocyclyl, or—OR⁸ (wherein R⁸ is heteroalkyl, heteroaralkyl, heterocyclyl, orheterocyclylalkyl) can be prepared by methods well known in the art. Forexample, 3-heterocyclylphenylacetic acid can be prepared under catalyticamination reaction conditions by reacting methyl 3-bromophenylacetatewith a suitable heterocycle (such as morpholine, piperidine,pyrrolidine, and the like) in the presence of a substituted phosphorousligand such as 2,2-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP) and apalladium catalyst such as tris(dibenzylideneacetone)dipalladium(Pd₂(dba)₃), followed by de-esterification of the resulting methyl3-heterocyclylphenylacetate under basic hydrolysis reaction conditions.

[0121] 3-(2-Aminoethyl)phenylacetic acid can be prepared by couplingmethyl 3-bromophenylacetate with nitroethylene under Heck reactionconditions to give methyl 3-(2-(nitrovinyl) phenyl acetate, followed byreduction of the alkene bond and the nitro group by methods well knownin the art, e.g. catalytic hydrogenation followed by hydride reduction.Hydrolysis of methyl 3-(2-aminoethyl)phenylacetate under basicconditions then provides 3-(2-aminoethyl) phenylacetic acid. It will berecognized by a person skilled in the art that the amino group in3-(2-aminoethyl)phenylacetic acid would be protected with a suitableprotecting group prior to reacting it with compound 2.

[0122] Compounds of formula 7 where R⁶ is —OR⁸ (wherein R⁸ isheteroaralkyl or heterocyclylalkyl) can be prepared by reactinghydroxyphenylacetic acid with an alkylating agent of formula R⁸X whereinR⁸ is as defined above and X is a leaving group under alkylationreaction conditions such as halo (Cl, Br, I), tosylate, mesylate,triflate, and the like. The reaction is typically carried out in thepresence of a base such as cesium carbonate, potassium carbonate and thelike, and in an aprotic polar organic solvent such as acetonitrile,N-methylpyrrolidine, and the like. Alkylating agents such as2-chloromethylpyridine, 2,2-dimethyl- 1,3-dioxolan-4-ylmethylp-toluenesulfonate, 1-(3-chloropropyl) piperidine, and4-(2-chloroethyl)morpholine, and the like are commercially available.

[0123] Compound 8 which is then converted to a compound of Formula (I)as described in Scheme I above. Again, as discussed above, a compound ofFormula (I) can be converted to other compounds of Formula (I). Forexample, acidic hydrolysis of compound (I) wherein R⁸ is2,2-dimethyldioxolan-4-ylmethyl provides a compound of Formula (I)wherein R⁸ is a 2,3-dihydroxy-propyl group (i.e., R⁸ is heteroalkylgroup).

[0124] Alternatively, compounds of Formula (I) where R³ is methyl andother groups are as defined in the Summary of the Invention can beprepared as shown in Scheme 3 below.

[0125] Reaction of a compound of formula 7 with a chlorinating agentsuch as oxalyl chloride in the presence of a catalytic amount ofdimethylformamide and in an inert solvent such as dichloromethane,chloroform, and the like, provides the acid chloride. Treatment of theacid chloride with aqueous ammonia at 0° C. provides phenylacetamide offormula 9. Coupling of 9 with methyl indoleglyoxalate 10 provides acompound of Formula (I). The coupling reaction is carried out in thepresence of a strong organic base such as tert-butoxide and in anethereal organic solvent such as tetrahydrofuran and the like. Compoundsof formula 10 where R¹ and R² vary can be prepared from 1-methylindoleby the procedures described in Faul, M., et. al., J. Org. Chem., 63,6053-6058, (1998).

[0126] A compound of Formula (I) can be converted to other compounds ofFormula (I) as described above. This synthetic route is particularlysuitable for preparing compounds of Formula (I) wherein R⁶ isheterocyclyl.

[0127] Alternatively, compounds of Formula (I) where R³ is methyl andother groups are as defined in the Summary of the Invention can beprepared as shown in Scheme 4 below.

[0128] Treatment of an iodobenzene of formula 11 withbis(pinacolato)diborane in the presence of a palladium catalyst such asPdCl₂(dppf), followed by coupling of the resulting borate with a4-bromo-3-(1-methylindol-3-ylmethyl)-1-methyl-pyrrole-2,5-dione 12 underSuzuki reaction conditions provides a4-phenyl-3-(1-methylindol-3-ylmethyl)-1-methylpyrrole-2,5-dione 13.Compounds of formula 12 can be prepared by methods well known in theart. For example, 4-bromo-3-(1-methylindol-3-yl)-1-methylpyrrole-2,5-dione can be prepared by method described inBrenner, M. et al., Tet. Lett., 44, 2887, (1988).

[0129] Treatment of 13 with a strong base such as sodium hydroxide,potassium hydroxide, and the like in an aqueous alcoholic solvent suchas ethanol provides a 4-phenyl-3-(1-methylindol-3-ylmethyl)-1-H-pyrrole-2,5-dione 8 which is then converted to a compound ofFormula (I) as described above.

[0130] Alternatively, compounds of Formula (I) where R³ is methyl andother groups are as defined in the Summary of the Invention can beprepared as shown in Scheme 5 below.

[0131] The acylation of N-methylindole of formula 1 with oxalyl chlorideas described above, followed by quenching with aqueous ammonium at 0° C.provides a compound of formula 14 Coupling of 14 with a methylphenylacetate of formula 15 provides a compound of Formula (I). Thecoupling reaction is carried out in the presence of a strong organicbase such as tert-butoxide and in an ethereal organic solvent such astetrahydrofuran and the like.

Utility, Testing, and Administration

[0132] Utility

[0133] The 3-indolyl-4-phenyl-1H-pyrrole-2,5-dione derivatives ofFormula (I) inhibit GSK-3β. The compounds and compositions containingthem are therefore useful in the treatment of diseases mediated byGSK-3β diseases such as Alzheimer's disease, obesity, diabetes,atherosclerotic cardiovascular disease, polycystic ovary syndrome,syndrome X, ischemia, traumatic brain injury, bipolar disorder,immunodeficiency and cancer.

[0134] In addition, Applicants have discovered that inhibition of GSK-3βactivity reduces the level of CD4+ T-helper 2 cells (Th2) which producecytokines such as IL-4, IL-5, IL-13, and promote IgE production andeosinophil differentiation. CD4 T-cells can differentiate intofunctionally distinct subsets with different profiles of cytokineproduction. Type 1 T Helper cells (Th1) produce IFN-g and IL-2 andpromote cell mediated immunity. Type 2 T Helper cells (Th2) produce IL-4and IL-5 and promote IgE production and eosinophil differentiation. Animbalance in the type of T-cell response appears to underlie thesusceptibility to asthma and allergic diseases. Through genetic studiesApplicants have discovered that GSK-3β controls the activity of TCF7(also known as TCF1 in the literature) thereby controlling whether ornot naive T-cells differentiate into Th1 or Th2 cells. Furthermore,Applicants have discovered that inhibitors of GSK-3β inhibit Th2 celldevelopment. This is an important discovery because it has beenestablished that Th2 specific cytokines play a key role in thepathogenesis of diseases such as allergies and asthma. Specifically,IL-13 is implicated in airway hyper-responsiveness and mucushypersecretion, as shown in murine studies of IL-13 delivery to thelungs of mice (Wills-Karp, M. et al., Science 282, 2258-2261 (1998);Grunig, G. et al., Science 282, 2261-2263 (1998)). Also, increasedexpression of IL-13 has been observed in airways of asthma patientswhich supports a role for IL-13 in the disease (Kroegel, C., et al.,European Respiratory Journal, 9, 899-904, (1996). Furthermore, the totalserum IgE levels and tissue eosinophilia, characteristic conditions ofallergy and asthma, correlate with disease severity in atopic asthmapatients (Yssel, H. et al., Clinical and Experimental Allergy, 28, Suppl5: 104-109 (1998)). Prior to Applicants' discovery that GSK-3β controlsTCF7 and thereby modulates Th2 cell differentiation, it was not knownthat inhibition of GSK-3β would provide a general method of treatingdieseases such as asthma (particularly atopic asthma), allergies,allergic rhinitisis, all of which are caused by an excess of Th2 cellsand there associated cytokines. As shown in the Examples below,Applicants have confirmed the ability of GSK-3β inhibitors to treat theasthmatic response in a variety of art-accepted in vivo models.Therefore, Applicants' invention encompasses the use of inhibitors ofGSK-3β to treat wide range of allergies, asthma, and other diseasescharacterized by excess Th2 cytokines.

[0135] A murine genetic approach was used to identify a genetic locusthat differentially regulated CD4 T cell subset differentiation andresponsiveness to IL-12. The genetic background of the murine straininfluences CD4 T cell development. The development of Th2 cells isfavored in one strain (Balb/C) of mice, while T cells from anotherstrain (B 10.D2) have a greater capacity to maintain IL-12responsiveness and Th1 development in vivo and in vitro. Analysis ofexperimental intercrosses between Balb/C and B10.D2 mice expressingtransgenic T cell antigen receptors led to identification of a locuslocated within a 0.5 cM region of murine chromosome 11 which controlsmaintenance of IL-12 responsiveness (Guler M. L. et al., J. Immunol.162, 1339-1347, 1999). This region was syntenic to the locus on humanchromosome 5q31, which has been associated with elevated serum IgElevels and susceptibility to asthma (Review: Cookson, W., Nature 402,Suppl. B5-B11, 1999). Positional cloning of this genetic locus wasperformed by analysis of the chromosomal sequence within thischromosomal region, and by analysis of gene expression.

[0136] We have demonstrated that TCF7 regulates T helper celldifferentiation. TCF7, which is expressed only in T cells, was shown tobe expressed in resting murine Th1, but not Th2 cells. This factor wasalso induced by IFN-gamma (FIG. 2B); and recognition elements for TCF7were found in the promoter regions of genes expressed in Th1 cells;IFN-gamma, IFN-alpha, IL-18 and the beta-2 subunit of the IL12 receptor.We have also shown that inhibition of GSK-3β will increase the level ofβ-catenin in T cells. β-catenin does then accumulate in the nucleus andact as cofactor for TCF7 to activate gene transcription (Example 2, FIG.1). Therefore, GSK-3β inhibitors will inhibit Th2 cell development.Wehave confirmed this by demonstrating that Th2 cytokine levels arereduced in cells treated with GSK-3β inhibitors (Examples 3 and 4).

[0137] Preferably, the GSK-3β inhibitors used for treatment of diseasescharacterized by excess Th2 cytokines will be selective for GSK-3βrelative to other kinases, particularly PKC, p38 kinase, lck and cdk2,by a ratio of at least 10:1, more preferably 100:1 (based on theirrespective IC50's). Determination of the relative IC50's of a putativeinhibitor may be accomplished by standard kinase activity assays wellknown to one of skill in the art. Such selective modulation permits theselective treatment of diseases characterized by excess Th2 cellproduction without affecting biological processes mediated by otherkinases

[0138] Furthermore, since GSK-3α and GSK-3β isoforms have 95% identicalcatalytic domains, it is contemplated that the compounds of the presentinvention would be useful in treating diseases mediated by GSK-3α.

[0139] Testing

[0140] The ability of the compounds of Formula (I) to inhibit GSK-3β wasmeasured by in vitro assays such as ligand binding assay and inhibitionof β-catenin degradation assay as described in detail in BiologicalExample 1 and 2 below. The ability of the compounds of this invention toinhibit secretion of IL-4 and IL-13 from human T-cells was measured byin vitro assay described in detail in Biological Example 3 below. Theability of the compounds of this invention to inhibit secretion of IL-4,IL-5 and IL-13 from murine T-cells was measured by in vitro assaydescribed in detail in Biological Example 4 below. The ability of thecompounds of this invention to inhibit leukocyte infiltration into thelungs was measured by in vivo assay described in detail in BiologicalExample 5 below. The ability of the compounds of this invention toreduce the IgE levels was measured by in vivo assay described in detailin Biological Example 6 below.

[0141] Administration and Pharmaceutical Composition

[0142] In general, the compounds of this invention will be administeredin a therapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of the compound of this invention, i.e., the active ingredient,will depend upon numerous factors such as the severity of the disease tobe treated, the age and relative health of the subject, the potency ofthe compound used, the route and form of administration, and otherfactors. The drug can be administered more than once a day, preferablyonce or twice a day.

[0143] Therapeutically effective amounts of compounds of Formula (I) mayrange from approximately 1 mg to 5 mg per kilogram body weight of therecipient per day; preferably about 3 mg/kg/day. Thus, foradministration to a 70 kg person, the dosage range would be about 70 to350 mg/day, most preferably be about 200 mg per day.

[0144] In general, compounds of this invention will be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions. Another preferred manner for administering compounds ofthis invention is inhalation. This is an effective method for deliveringa therapeutic agent directly to the respiratory tract for the treatmentof diseases such as asthma and similar or related respiratory tractdisorders (see U.S. Pat. No. 5,607,915).

[0145] The choice of formulation depends on various factors such as themode of drug administration and bioavailability of the drug substance.For delivery via inhalation the compound can be formulated as liquidsolution, suspensions, aerosol propellants or dry powder and loaded intoa suitable dispenser for administration. There are several types ofpharmaceutical inhalation devices-nebulizer inhalers, metered doseinhalers (MDI) and dry powder inhalers (DPI). Nebulizer devices producea stream of high velocity air that causes the therapeutic agents (whichare formulated in a liquid form) to spray as a mist which is carriedinto the patient's respiratory tract. MDI's typically are formulationpackaged with a compressed gas. Upon actuation, the device discharges ameasured amount of therapeutic agent by compressed gas, thus affording areliable method of administering a set amount of agent. DPI dispensestherapeutic agents in the form of a free flowing powder that can bedispersed in the patient's inspiratory air-stream during breathing bythe device. In order to achieve a free flowing powder, the therapeuticagent is formulated with an excipient such as lactose. A measured amountof the therapeutic agent is stored in a capsule form and is dispensedwith each actuation.

[0146] Recently, pharmaceutical formulations have been developedespecially for drugs that show poor bioavailability based upon theprinciple that bioavailability can be increased by increasing thesurface area i.e., decreasing particle size. For example, U.S. Pat. No.4,107,288 describes a pharmaceutical formulation having particles in thesize range from 10 to 1,000 nm in which the active material is supportedon a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684describes the production of a pharmaceutical formulation in which thedrug substance is pulverized to nanoparticles (average particle size of400 nm) in the presence of a surface modifier and then dispersed in aliquid medium to give a pharmaceutical formulation that exhibitsremarkably high bioavailability.

[0147] The compositions are comprised of in general, a compound ofFormula (I) in combination with at least one pharmaceutically acceptableexcipient. Acceptable excipients are non-toxic, aid administration, anddo not adversely affect the therapeutic benefit of the compound ofFormula (I). Such excipient may be any solid, liquid, semi-solid or, inthe case of an aerosol composition, gaseous excipient that is generallyavailable to one of skill in the art.

[0148] Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

[0149] Compressed gases may be used to disperse a compound of thisinvention in aerosol form. Inert gases suitable for this purpose arenitrogen, carbon dioxide, etc. Other suitable pharmaceutical excipientsand their formulations are described in Remington's PharmaceuticalSciences, edited by E. W. Martin (Mack Publishing Company, 18th ed.,1990).

[0150] The amount of the compound in a formulation can vary within thefull range employed by those skilled in the art. Typically, theformulation will contain, on a weight percent (wt %) basis, from about0.01-99.99 wt % of a compound of Formula (I) based on the totalformulation, with the balance being one or more suitable pharmaceuticalexcipients. Preferably, the compound is present at a level of about 1-80wt %. Representative pharmaceutical formulations containing a compoundof Formula (1) are described below.

EXAMPLES

[0151] The following preparations and examples are given to enable thoseskilled in the art to more clearly understand and to practice thepresent invention. They should not be considered as limiting the scopeof the invention, but merely as being illustrative and representativethereof.

[0152] Abbreviations used in the examples are defined as follows: “HCl”for hydrochloric acid, “DMF” for dimethylformamide, “NaOH” for sodiumhydroxide, “KOH” for potassium hydroxide, “DMSO” for dimethylsulfoxide,“NaHCO₃” for sodium bicarbonate, “NaCl” for sodium chloride, “K₂CO₃” forpotassium carbonate, “Na₂CO₃” for sodium carbonate, “LiOH” for lithiumhydroxide, “Et₃N” for triethylamine, “NH₃ (aq)” for ammonium hydroxide,“CH₂Cl₂” for methylene chloride, “MeOH” for methanol, “EtOH” forethanol, “Ph₃P” for triphenylphosphine, “C_(S)CO₃” for cesium carbonate,“BINAP” for 2,2-bis-(diphenylphosphino)-1,1′-binaphthyl, “Pd₂(dba)₃” fortris(dibenzylideneacetone)-dipalladium, “NaCNBH₃” for sodiumcyanoborohydride, “THF” for tetrahydrofuran, “Na₂SO₄” for sodiumsulfate, “RT” for room temperature, “PTLC” for preparatory thin layerchromatography, “SiO₂” for silica gel, “EtOAc” for ethyl acetate, “APMA”for aminophenyl-mercuric acetate, “IL-1” for interleukin-1, and “RPMI”for Roswell Park Memorial Institute.

Synthetic Examples Example 1 Synthesis of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione

[0153]

[0154] Step 1

[0155] Thionyl chloride (17 mL, 0.64 mol) was added dropwise to methanolat 0° C. After the completion of the addition, the reaction mixture wasstirred at 0° C. for 10 min., and then 3-hydroxyphenylacetic acid (25 g,0.16 mol) was added. The resulting reaction mixture was stirred at roomtemperature for 2h. Volatiles were removed and the residue waspartitioned between water and ethyl acetate. The organic layer wasseparated, washed with H₂O, NaHCO₃, and NaCl (sat.) and dried overNa₂SO₄. The crude product was purified on a silica gel column with 20%EtOAc in hexane to give methyl 3-hydroxyphenylacetate as a colorless oil(25 g, 94% yield).

[0156] Step 2

[0157] Methyl 3-hydroxyphenylacetate (20 g, 0.12 mol),(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl ρ-tosylate (51.7 g, 1.5 eq.)and K₂CO₃ (50 g, 3 eq.) in N-methylpyrrolidinone was heated at 96° C.overnight. The reaction mixture was cooled to room temperature, quenchedwith H₂O, and partitioned between H₂O and EtOAc. The organic layer wasseparated, washed with H₂O and NaCl (sat.), and then dried over Na₂SO₄.The crude product was purified on a silica gel column with 20% EtOAc inhexane to give methyl3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetate as an oil(23 g, 68% yield).

[0158] Step 3

[0159] To a solution of methyl3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl-acetate (23 g,0.08 mol) in methanol (80 mL) and water (5 mL) was added LiOH-H₂O (13.8g, 4 eq.). After stirring the reaction mixture at room temperature for 4h, the volatiles were removed under vacuo and the residue waspartitioned between EtOAc and H_(2O). The aqueous layer was separated,cooled with an ice bath, and then acidified with 10% aq. HCl. The acidicaqueous layer was extracted with EtOAc. The EtOAc layer was washed withNaCl (sat.), dried over Na₂SO₄, and concentrated to give3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetic acid as awhite solid (22 g,>99% yield).

[0160] Step 4

[0161] Oxalyl chloride (1.05 eq., 4.15 mL) was added dropwise to asolution of N-methylindole (5.8 mL, 50 mmol) in diethyl ether (395 mL)at 0° C. Yellow precipitates were formed. After the completion of theaddition, the reaction mixture was stirred at 0° C. for 30 min., andthen the volatiles were removed under vacuo. The residue wasre-dissolved in dichloromethane (375 mL) and added to a solution of3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenylacetic acid (13.3g, 50 mmol) and Et₃N (12.5 mL, 2.2 eq.) in dichloromethane (375 mL) at0° C. The resulting mixture was stirred at 0° C. and then allowed towarmed up slowly to room temperature. After stirring overnight, thevolatiles were removed and the residue was purified on a silica gelcolumn with dichloromethane to give3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]furan-2,5-dione(5.4 g, 27% yield).

[0162] Step 5

[0163]3-(1-Methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-phenyl]furan-2,5-dione(5.4 g, 13.7 mmol) was dissolved in DMF (50 mL) and was diluted with NH₃(aq.) (100 mL). The reaction mixture was then heated at 140° C. for 5 h,cooled to room temperature and then diluted with water. The product wasextracted with EtOAc and the organic layer was washed with NaCl (sat.)and dried over sodium sulfate to give the crude product which wasfurther purified by re-crystallization from dichloromethane and hexaneto give 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione (5 g).

[0164]¹H NMR (DMSO-d6): δ 11.08 (s, NH), 8.04 (s, 1H), 7.49 (d, 1H,J=8.2), 7.22 (t, 1H, J=8.0), 7.12 (t, 1H, J=7.0), 6.97 (m, 3H), 6.76 (t,1H, J=7.5), 6.33 (d, 1H, J=8.0), 4.23 (m, 1H), 3.96 (dd, 1H, J=6.5,8.4), 3.91 (s, 3H), 3.77 (d, 1H, J=5.1), 3.60 (dd, 1H, J=6.1, 8.2), 1.30(s, 3H), 1.27 (s, 3H); MS (EI): M⁺432.

[0165] Following the procedure described above, but substituting3-hydroxyphenylacetic acid with 2-hydroxyphemylacetic acid gave3-(1-methylindol-3-yl)-4-[2-((RS)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione. ¹H NMR (DMSO-d6): δ 10.99 (s, NH), 8.03(s, 1H), 7.46 (d, 1H, J=7.2), 7.38 (t, 1H, J=5.4), 7.27 (d, 1H, J=7.5),7.11 (t, 1H, J=7.1), 7.03 (m, 2H), 6.64 (t, 1H, J=7.1), 6.32 (d, 1H,J=7.1), 4.3 (br.s. 2H), 3.88 (s, 3H), 3.68 (br.s. 2H), 3.2 (br.s. 1H),1.19 (s, 6H); m.p. 220.8-221.2° C.; MS (EI): M⁺432;

[0166] Following the procedure described above, but substituting3-hydroxyphenylacetic acid with 4-hydroxyphenylacetic acid gave3-(1-methylindol-3-yl)4-[4-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione. ¹H NMR (DMSO-d6): δ 11.00 (s, NH), 7.97(s, 1H), 7.48 (d, 1H, J=6.3), 7.36 (d, 2H, J=8.9), 7.13 (t, 1H, J=7.2),6.90 (d, 2H, J=8.9), 6.78 (t, 1H, J=7.2), 6.42 (d, 1H, J=8.0), 4.39 (m,1H), 4.06 (m, 3H), 3.90 (s, 3H), 3.73 (m, 1H), 1.35 (s, 3H), 1.30 (s,3H); MS (EI): M⁺432.

[0167] Following the procedure described above, but substituting(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-tosylate with(S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-tosylate gave3-(1-methylindol-3-yl)-4-[3-((S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione.

Example 2 Synthesis of3-(1-methylindol-3-yl)-4-{3-[((R)-2-hydroxy-2-hydroxymethyl)ethyloxy]phenyl}-1H-

[0168]

[0169] Step 1

[0170] Toluenesulfonic acid (100 mg) was added to a solution of3-(1-methylindol-3-yl)4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dione(4.3 g) in methanol (100 mL) and water (10 mL) and the reaction mixturewas heated at 50 ° C. overnight. The volatiles were removed and theresidue was partitioned between water and EtOAc. The organic layer waswashed with NaCl (sat.) and dried over sodium sulfate. The crude productwas purified on a silica gel column with 5% MeOH in CH₂Cl₂ and furtherpurified by recrystallization from CH₂Cl₂/hexane to give3-(1-methylindel-3-yl)-4-{3-[((R)-2-hydroxy-2-hydroxymethyl)ethyloxy]phenyl}-1H-pyrrole-2,5-dione(2.46 g). ¹H NMR (DMSO-d6): δ 11.05 (s, NH), 8.03 (s, 1H), 7.48 (d, 1H,J=8.2), 7.15 (m, 1H), 7.02 (s, 1H), 6.92 (m, 1H), 6.92 (m, 1H), 6.76 (t,1H, J=7.3), 6.37 (t, 1H, J=8.0), 4.89 (d, OH, J=4.7), 4.61 (t, OH,J=5.8), 3.90 (s, 3H), 3.85 (m, 1H), 3.72 (m, 2H), 3.37 (m, 2H); MS (EI):M⁺392; m.p. 177.7-178.0° C.; Anal (C₂₂H₂₀N₂O₅-0.15H₂O): C, H, N.

[0171] Following the procedure described above but substituting3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionewith3-(1-methylindol-3-yl)-4-[2-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionegave 3-( 1-methylindol-3-yl)-4-{2-[(-2-hydroxy-2-hydroxymethyl)ethyloxy]-phenyl}-1H-pyrrole-2,5-dione.

[0172]¹H NMR (DMSO-d6): δ 10.96 (s, NH), 7.98 (s, 1H), 7.47 (d, 1H,J=8.1), 7.36 (t, 1H, J=8.8), 7.23 (d, 1H, J=7.2), 7.11 (t, 1H, J=7.1),6.95 (m, 2H), 6.66 (t, 1H, J=7.3), 6.33 (d, 1H, J=8.0), 3.87 (s, 3H),3.6 (br.s. 1H), 3.2 (br.s. 2H), 3.1 (br.s. 2H); m.p. 245.0-247.1° C.; MS(EI): M⁺392; Anal (C₂₂H₂₀O₅N₂-1.20H₂O): C, N, H.

[0173] Following the procedure described above but substituting3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionewith3-(1-methylindol-3-yl)-4-[4-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionegave 3-(1-methylindol-3-yl)-4-{4-[((R)-2-hydroxy-2-hydroxymethyl)ethyloxy]-phenyl}-1H-pyrrole-2,5-dione.¹H NMR (DMSO-d₆): δ 11.00 (s, NH), 7.97 (s, 1H), 7.48 (t, 1H, J=8.2),7.34 (d, 2H, J=8.9), 7.13 (t, 1H, J=7.2), 6.87 (d, 2H, J=8.9), 6.86 (t,1H, J=7.2), 6.43 (d, 1H, J=8.1), 4.00 (m, 1H), 3.90 (s, 3H), 3.8 (m,2H), 3.43 (m, 2H); m.p. 220.3-222.7° C.; MS (EI): M⁺392.

[0174] Following the procedure described above, but substituting3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionewith 3-(1-methylindol-3-yl)-4-{3-((S)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)phenyl]-1H-pyrrole-2,5-dionegave 3-(1-methylindol-3-yl)-4-{3-[((S)-2-hydroxy-2-hydroxymethyl)ethyloxy]-phenyl}-1H-pyrrole-2,5-dione.MS (EI): M⁺392; m.p. 176.9-178.1° C.

Example 3 Synthesis of3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1H-pyrrole-2,5-dione

[0175]

[0176] Step 1

[0177] To a stirred solution of 3-iodophenol (2.2g, 10 mmol),N-(2-hydroxyethyl)morpholine (2 eq. 2.4 mL) and Ph₃P (2 eq. 5.24 g) inTHF (90 mL)at 0° C. was added dropwise a solution ofdiisopropylazodicarboxylate (2 eq. 3.96 g) in THF (20 mL). The resultingsolution was stirred at room temperature overnight and was then quenchedwith NaHCO₃. The product was extracted with EtOAc and the EtOAc layerwas washed with NaCl (sat.), dried over sodium sulfate. The crudemixture was then purified on a silica gel column with 25% acetone inhexane to give 3-(2-morpholin-4-ylethyloxy) iodobenzene (2.8 g, 84%yield).

[0178] Step 2

[0179] A flask charged with 3-(2-morpholin-4-ylethyloxy)iodobenzene(0.33 g, 1 mmol), bis(pinacolato)diboron (0.279 g, 1.1 mmol), potassiumacetate (0.294 g, 3 mmol) and PdCl₂(dppf) (48 mg, 0.06 mmol) was flushedwith nitrogen. N,N-Dimethylformamide (6 mL) was added and the reactionmixture was stirred at 80° C. for 3 h and then cooled to roomtemperature. 3-Bromo-4-(1-methylindol-3-yl) -1-methylpyrrole-2,5-dione(0.255 g, 0.8 mmol) ((synthesized according to the procedures describedin Brenner, M. et al., Tet. Lett. 44, 2887, (1988)) was added to thereaction mixture, followed by the addition of PdCl₂(dppf) (48 mg, 0.06mmol)) and 2M aq. Na₂CO₃ (2.5 mL). The resulting mixture was stirred at80° C. for 2.5 h, then cooled to room temperature, and quenched withH₂O. The product was extracted with EtOAc. The EtOAc layer was washedwith H₂O, NaCl (sat.), dried over Na₂SO₄, and concentrated. Purificationof the crude product on a silica gel column with 2/3/5 ofacetone/CH₂Cl₂/hexane gave3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)-phenyl]-1-methylpyrrole-2,5-dioneas an orange-red oil. (0.25 g, 70% yield).

[0180] Step 3

[0181]3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1-methylpyrrole-2,5-dione(0.22 g, 0.5 mmol) was dissolved in EtOH (10 mL) and a solution of KOH(1.5 g) in H₂O (2.5 mL) was added. After the reaction mixture wasrefluxed for 3 h, it was cooled to room temperature, followed byevaporation of EtOH. The residue was acidified with aq. HCl to pH=4.5.The product was extracted with EtOAc and the EtOAc layer was dried oversodium sulfate and concentrated to give3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dionewhich was in the next step without further purification.

[0182] Step 4

[0183]3-(1-Methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]furan-2,5-dionewas then dissolved in DMF (5 mL) and ammonium hydroxide (10 mL) wasadded. The resulting mixture was heated at 140° C. for 4 h, then cooledto room temperature, and diluted with water. The product was extractedinto EtOAc. The EtOAc layer was washed with NaCl (sat.) and dried oversodium sulfate. Purificaiton on a silica gel column with 5% (10% NH₄OHin MeOH) in CH₂Cl₂ gave 3-(1-methylindol-3-yl)-4-[3-(2-morpholin-4-ylethyloxy)phenyl]-1H -pyrrole-2,5-dione (0.21g, >99% yield).

[0184]¹H NMR (CDCl₃): δ 7.95 (s, 1H), 7.41 (br.s. NH), 7.32 (d, 1H,J=7.2), 7.17 (m, 3H), 7.02 (s, 1H), 6.91 (d, 1H, J=6.5), 6.83 (t, 1H,J=7.1), 6.40 (d, 1H, J=8.1), 3.92 (br.s. 2H), 3.90 (s, 3H), 3.78 (br.s.4H), 2.65 (br.s. 2H), 2.51 (br.s. 4H); MS (EI): M⁺431; Anal(C₂₅H₂₅O₄N₃-0.3H₂O): C, H, N.

[0185] Following the procedure described above, but substituting3-bromo-4-(1-methylindol-3-yl)-1-methylpyrrole -2,5-dione with3-bromo-4-(1H-indol-3-yl)-1-methylpyrrole-2,5-dione, provided3-(1H-indol-3-yl)-4-[3-(2-morpholin-4-ylethoxy)phenyl]-1H-pyrrole-2,5-dione. MS (EI):M⁺417.

Example 4 Synthesis of3-(1-methylindol-3-yl)-4-(3-morpholin-4-ylphenyl)-1H -pyrrole-2,5-dione

[0186]

[0187] Step 1

[0188] A round bottom flasked flushed with argon was charged with methyl3-bromophenyl-acetate (2.29 g, 10 mmol) (prepared from3-bromophenylacetic acid as described in example 2, step 1), morpholine(1.05 mL, 1.2 eq.), CsCO₃ (4.55 g, 1.4 eq.), Pd₂(dba)₃ (92 mg, 0.01 eq)and BINAP (93 mg, 0.15 eq.) in toluene (20 mL). The resulting mixturewas heated at 100° C. overnight and then diluted with diethyl ether (120mL). The precipitates were filtered through a Celite pad and thefiltrate was concentrated and purified on a silica-gel column with 20%EtOAc in hexane to give methyl 3-(morpholin-4-yl)phenylacetate (0.55 g,23%).

[0189] Step 2

[0190] To a solution of methyl 3-(morpholin-4-yl)phenylacetate (0.50 g,2.1 mmol) in methanol (5 mL) and H₂O (1 mL) was added lithium hydroxidemonohydrate (0.18 g, 2 eq.). After the reaction mixture was stirred atroom temperature overnight, it was concentrated to dryness. Acetic acidwas then added to the residue and the resulting mixture was partitionedbetween EtOAc and H₂O. The organic layer was washed with NaCl (sat.),dried over Na₂SO₄, and evaporation under vacuo to give3-(morpholin-4-yl)phenylacetic acid (0.42 g).

[0191] Step 3

[0192]3-(Morpholin-4-yl)phenylacetic acid (0.42 g, 1.9 mmol) wasdissolved in CH₂Cl₂ (5 mL) and oxalyl chloride (0.22 mL, 1.2 eq.) wasadded. The reaction mixture was stirred at room temperature for 2 h andthen cooled to 0° C. Ammonium hydroxide solution (2 mL) was addeddropwise. Volatiles were removed and the crude mixture was dissolved inmethanol, stirred, and filtered. The filtrate was concentrated to give3-(morpholin-4-yl)benzylamide (0.5 g) which was in the next step withoutany further purification).

[0193] Step 4

[0194] To a suspension of 3-(morpholin-4-yl)benzylamide (0.5 g) andmethyl indoleglyoxalate (0.55g, 2.5 mmol) in THF at 0° C. was addedpotassium tert-butoxide (1.0 M, 3.45 mL, 3.45 mmol) dropwise. Thereaction mixture which turned orange in color was stirred at 0° C. for1h and then allowed to warm to room temperature. After stirringovernight, the reaction mixture was quenched with H₂O and extracted withEtOAc. The organic layer was washed with NaCl (sat.), and dried overNa₂SO₄. Preparative TLC purificaiton with 5% MeOH in CH₂Cl₂ gave3-(1-methylindol-3-yl)-4-(3-morpholin -4-ylphenyl)-1H-pyrrole-2,5-dione(150 mg) as an oil which was converted to the hydrochloride salt andrecrystallized from EtOAc to give3-(1-methylindol-3-yl)-4-(3-morpholin-4-ylphenyl) -1H-pyrrole-2,5-dionehydrochloride (72 mg) as a solid.

[0195]¹H NMR (DMSO-d6): δ 11.02 (s, NH), 8.02 (s, 1H), 7.48 (d, 1H,J=8.1), 7.15 (m, 2H), 6.90 (m, 2H), 6.74 (t, 1H, J=7.4), 6.34 (d, 1H,J=8.1), 3.90 (s, 3H), 3.62 (m, 4H), 2.8 (m, 4H); MS (LSIMS): (M+H)⁺388.

[0196] Following the procedure described above, but substitutingmorpholine with pyrrolidine in Step 1,3-(1-methylindol-3-yl)-4-(3-pyrrolidin-1-ylphenyl)-1H-pyrrole-2,5-dionewas prepared. MS (EI): M⁺372.

Example 5 Synthesis of3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)phenyl]-1H-pyrrole-2,5-dione

[0197]

[0198] Step 1

[0199] To a solution of methyl 3-hydroxyphenyl acetate (2.49 g, 15 mmol)and 1-bromo-3-chloropropane (2.96 mL, 2 eq.) in acetonitrile (50 mL) wasadded cesium carbonate (5.4 g, 1.1 eq.). The reaction mixture wasrefluxed for 24 h, then cooled to room temperature and filtered througha Celite pad. The filtrate was concentrated and the residue was purifiedon a silica gel column with 5/55/40 of MeOH/CH₂Cl₂/hexane to give methyl3-(3-chloro-propyloxy)phenyl acetate (4.2 g) as an oil.

[0200] Step 2

[0201] To a solution of methyl 3-(3-chloropropyloxy)phenyl acetate (2.87g, 10 mmol) in methanol (15 mL) was added LiOH-H₂0 (0.84 g, 2 eq.). Thereaction mixture was stirred at room temperature for 2 h. Volatiles wereremoved and the residue was partitioned between EtOAc and water. Theaqueous layer was acidified and extracted with EtOAc. The combined EtOAclayers were washed with NaCl (sat.), dried over Na₂SO₄ and concentratedto give 3-(3-chloropropyloxy)phenylacetic acid (2.8 g).

[0202] Step 3

[0203] To a solution of N-methylindole (1.16 mL, 9.1 mmol) in diethylether (70 mL) at 0° C. was added dropwise oxalyl chloride (0.83 mL, 1.1eq.). After the additon, the reaction mixture was stirred at 0° C. for15 min., and the volatiles were removed under vacuo. The residue wasre-dissolved in dichloromethane (70 mL) and triethylamine (2.3 mL, 2eq.) was added. The reaction mixture was cooled to 0° C. and a solutionof 3-(3-chloro-propyloxy)phenylacetic acid (2.73 g, 10 mmol) indichloromethane (70 mL) was added dropwise. The resulting mixture wasstirred at 0° C., and then allowed to warm up to room temperatureovernight. Volatiles were removed under vacuo and the residue waspurified on a silica gel column with dichloromethane to give3-(1-methylindol-3-yl)-4-[3-(3-chloropropyloxy)phenyl]furan-2,5-dione(1.1 g).

[0204] Step 4

[0205] To a solution of3-(1-methylindol-3-yl)-4-[3-(3-chloropropyloxy)phenyl]furan-2,5-dione(1.0 g, 2.2 mmol) in DMF (15 mL) was added sodium azide (0.43 g, 3 eq.)and the resulting mixture was heated at 75° C. for 24 h. The reactionmixture was cooled to room temperature and quenched with water. Theproduct was then extracted into EtOAc. The EtOAc layer was washed withH₂O, NaCl (sat.), dried over Na₂SO₄, and concentrated in vacuo to give3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy) phenyl]furan-2,5-dione(1.0 g) which was used directly in the next step without any furtherpurification.

[0206] Step 5

[0207] To a solution of3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]furan-2,5-dione(1.0 g) in DMF (7 mL) was added and ammonium hydroxide (50 mL). Thereaction mixture was heated at 140° C. for 3.5 h, then cooled to roomtemperature and diluted with water. The precipitates were filtered anddried to give3-(1-methylindol-3-yl)4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione(0.58 g). MS (EI): M⁺401.

[0208] Step6

[0209] To a solution of3-(1-methylindol-3-yl)-4-[3-(3-azidopropyloxy)phenyl]-1H-pyrrole-2,5-dione(0.4 g, 1 mmol) in THF (20 mL) was added Ph₃P (0.25 g, 1.1 eq.),followed by the H₂O (0.017 mL). The resulting mixture was stirred atroom temperature for 48 h and then concentrated in vacuo. The residuewas purified on a silica gel column with 8% (10% NH₄OH in methanol) inCH₂Cl₂ to give 3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)-phenyl]-1H-pyrrole-2,5-dione (0.35 g) which wasconverted to HCl salt and recrystalized to give3-(1-methylindol-3-yl)-4-[3-(3-aminopropyloxy)-phenyl]-1H-pyrrole-2,5-dione(0.21 g) as the HCl salt.

[0210] 1H NMR (DMSO-d6): δ 11.1 (s, NH), 8.06 (s, 1H), 7.50 (d, 1H,J=8.2), 7.20 (m, 2H), 6.91 (m, 2H), 6.73 (t, 1H, J=7.2), 6.33 (d, 1H,J=8.0), 3.93 (m, 2H), 3.91 (s, 3H), 3.67 (br.s. 2H), 1.85 (m, 2H); MS(EI): M⁺375.

Example 6 Synthesis of3-(1-methylindol-3-yl)-4-[3-(2-aminoethyloxy)phenyl]-1H-pyrrole-2,5-dione

[0211]

[0212] Step 1

[0213] To a stirred solution of methyl 3-hydroxyphenylacetate (1.66 g,10 mmol), 2-chloroethanol (1.34 mL, 2 eq.) and triphenylphosphine (5.24g, 2 eq.) in THF (100 mL) at 0° C. was added dropwisediisopropylazodicarboxylate (3.96 mL, 2 eq.) and the resulting mixturewas stirred at room temperature overnight. The reaction mixture was thenquenched with NaHCO₃ and the product was extracted with EtOAc. The EtOAclayers were washed with brinebrine, dried over sodium sulfate, andconcentrated. Purification on a silica gel column with 10% EtOAc inhexane gave methyl 3-(2-chloroethyloxy) phenylacetate (1.6 g, 70% yield)which was converted to 3-(1-methylindol-3-yl)-4-[3-(2-aminoethyloxy)phenyl]-1H-pyrrole-2,5-dione by following the procedure described inExample 5, Steps 2-6 above.

[0214]¹H NMR (DMSO-d6): δ 11.11 (s, NH), 8.22 (br.s. NH2), 8.05 (s, 1H),7.49 (d, 1H, J=8.2), 7.20 (m, 1H), 7.12 (s, 1H), 6.99 (dd, 1H, J=2.6,8.3), 6.90 (d, 1H, J=7.8), 6.75 (t, 1H, J=7.3), 6.35 (d, 1H, J=8.1),4.09 (t, 2H, J=5.0), 3.91 (s, 3H), 3.15 (br.s. 2H); MS (LSIMS):(M+H)⁺362; Anal (C₂₁H₂₀N₃O₃Cl-0.85H₂O): C, H, N.

Example 7 Synthesis of3-(1-methylindol-3-yl)-4-{3-[(2-(RS)-hydroxy-2-hydroxymethyl)ethylamino]phenyl}-1H-pyrrole-2,5-dione

[0215]

[0216] Step 1

[0217] Oxalyl chloride (4.9 mL, 56 mmol) was added dropwise to a stirredsolution of 1-methylindole (6.5 mL, 51 mmol) in ether (350 mL) at 0° C.After the completion of the addition, the reaction mixture was stirredat 0° C. for 30 min., and then the volatiles were removed under reducedpressure to afford 1-methylindole-3-glyoxylyl chloride.

[0218] Step 2

[0219] A solution of 1-methylindole-3-glyoxylyl chloride indichloromethane (350 mL) was added to a solution of 3-nitrophenylaceticacid (8.5 g, 0.093 mL) and triethylamine (13 mL, 93 mmol) indichloromethane (350 mL) at 0° C. The reaction mixture was then stirredat room temperature overnight and then concentrate under reducedpressure. The crude product was purified on a silica gel column with 6:1hexane/ethyl acetate to afford3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 55%).

[0220] Step 3

[0221] A solution of3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione (9 g, 26 mmol)in DMF (20mL) was heated to about 140° C. Aqueous ammonia (20 mL) wasadded in portions and the heating was continued for 6 h. Water (20 mL)was added and the reaction mixture was allowed to stand at roomtemperature overnight. The orange colored solid was filtered off, washedwith water and dried under vacuum to afford3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (6.7 g,75%).

[0222] Step 4

[0223] To a solution of3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione (6.5 g, 19mmol) in acetone (500 mL), was added TiCl₃ (45 mL) in 5 portions at 30minute interval. The reaction mixture was stirred at room temperatureovernight and then neuteralized with 10N NaOH. The product was extractedwith EtOAc, dried, and concentrated. The crude product was purified on asilica gel column with 3% MeOH in CH₂Cl₂to afford3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole -2,5-dione (4.9 g,82.5%).

[0224] Step 5

[0225] A mixture of3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg,0.32 mmol) and 2,2-dimethyldioxolane4-carboxaldehyde (0.38 mmol)(prepared as described in Kumont, von R., et al. Helv. Chim. Acta., 66,814, (1983)) in dichloromethane (12 mL) was stirred at room temperaturefor 10 min., and then Na(OAc)₃BH (120 mg, 0.57 mmol) was added. Thereaction mixture was stirred overnight and then partition between EtOAcand H₂O. The organic layer was separated, washed with water andconcentrated. The crude product was purified by preparatory TLC with 3/1hexanes/EtOAc to give3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyldioxolan-4-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione (32.6 mg, 24%).

[0226] Step 6

[0227]3-(1-Methylindol-3-yl)-4-[3-(2,2-dimethyldioxolan-4-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione(30 mg) was dissolved in MeOH (5 mL) and H₂O (1 mL). Catalytic amount ofp-toluenesulfonic acid was added and the reaction mixture was stirred at50° C. overnight. The reaction mixture was concentrate and the residuewas purified by preparatory TLC to give 3-(1-methylindol-3-yl)-4-{3-[(2-(RS)-hydroxy-2-hydroxymethyl)ethylamino]phenyl}-1H-pyrrole-2,5-dione (18 mg, 66%). MS(EI): M⁺391

Example 8 Synthesis of3-(1-methylindol-3-yl)-4-(3-tetrahydropyran-4-ylaminophenyl)-1H-pyrrole-2,5-dione

[0228]

[0229] A mixture of3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg,0.32 mmol) and tetrahydro-4H-pyran-4-one (65 mg, 0.65 mmol) in MeOH (8mL) was stirred at room temperature for 40 min., and then NaCNBH₃ (63mg, 1.0 mmol) was added. After stirring the reaction mixture overnightthe volatiles were removed under vacuo and the residue was purified bypreparatory TLC (3% MeOH/CH₂Cl₂) to give3-(1-methylindol-3-yl)-4-(3-tetrahydropyran-4-ylaminophenyl)-1H-pyrrole-2,5-dione (88.2 mg, 70%). LC/MS: M⁺401(98.6%).

Example 9 Synthesis of3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyl-1,3-dioxan-5-ylamino)phenyl]-1H-pyrrole-2,5-dione

[0230]

[0231] A mixture of3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (200 mg,0.63 mmol) and 2,2-dimethyl-1,3-dioxane-5-one (98 mg, 0.76 mmol) in MeOH(10 mL) was stirred at room temperature for 15 min., and then NaCNBH₃(79 mg, 1.26 mmol) was added. After stirring the reaction mixtureovernight the volatiles were removed under vacuo and the residue waspurified by preparatory TLC (1% MeOH/CH₂Cl₂) to give3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyl-1,3-dioxan-5-ylamino)phenyl]-1H-pyrrole-2,5-dione (185 mg, 68%). MS(EI): M⁺431, MP: 201-203°C.

Example 10 Synthesis of3-(1-methylindol-3-yl)-4-[3-(1-(RS)-hydroxy-2-hydroxymethylethylamino)phenyl]-1H-pyrrole-2,5-dione

[0232]

[0233] A solution of3-(1-methylindol-3-yl)-4-[3-(2,2-dimethyl-1,3-dioxan-5-yl-amino)phenyl]-1H-pyrrole-2,5-dione (173 mg, 0.4 mmol) in MeOH (30 mL) and H₂O (3 mL) withcatalytic amount of ρ-toluenesulfonic acid was stirred at 50° C.overnight. The volatiles were removed under vacuo and the residue waspurified by preparatory TLC (3% MeOH/CH₂Cl₂) to afford3-(1-methylindol-3-yl)-4-[3-(1-(RS)-hydroxy-2-hydroxymethylethylamino)phenyl]-1H-pyrrole-2,5-dione (130 mg, 83%). MS(LSIMS): (M+H)⁺392, MP:97.5-101° C.

Example 11 Synthesis of3-(1-methylindol-3-yl)-4-[3-(imidazol-2-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione

[0234]

[0235] A mixture of3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg,0.32 mmol) and imidazole-2-carboxaldehyde (40 mg, 0.42 mmol) in MeOH (8mL) was stirred for 15 min., and then NaCNBH₃ (40.2 mg, 0.64 mmol) wasadded. After stirring the reaction mixture overnight the volatiles wereremoved under vacuo and the residue was purified by preparatory TLC (3%MeOH/CH₂Cl₂) to afford3-(1-methylindol-3-yl)-4-[3-(imidazol-2-ylmethylamino)phenyl]-1H-pyrrole-2,5-dione (24.8 mg, 20 %). LC/MS: M⁺397(94.2%).

Example 12 Synthesis of3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldimethylsilyloxypropylamino)phenyl]-1H-pyrrole-2,5-dione

[0236]

[0237] Step 1

[0238] Tetrapropylammonium perruthenate (0.18 g, 5.3 mmol) was added toa mixture of methylene chloride (20 mL) and acetonitrile (2 mL)containing 3-(tert-butyldimethylsilyloxy)-propanol (2 g, 0.01 mmol),N-methylmorpholine N-oxide (1.76 g) and 4 Å molecular sieves. Thereaction mixture was stirred at RT overnight and then filtered through apad of silica gel. The filtrate was concentrated under vacuo to afford3-(tert-butyldimethylsilyloxy)-propionaldehyde (1.3 g, 66%).

[0239] Step 2

[0240] A mixture of3-(l-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g, 6mmol) and 3-(tert-butyldimethylsilyloxy)propionaldehyde (0.25 g,13 mmol)in CH₂Cl₂ (10 mL) and MeOH (5 mL) was stirred at room temperature for 15min and then NaCNBH₃ (57 mg, 1.5 eq) was added. The reaction mixture wasstirred at RT overnight and then concentrated under vacuo. The residuewas purified by preparatory TLC to give 98 mg 3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldimethylsilyloxypropylamino)phenyl]-1H-pyrrole-2,5-dione(32%) MS (LSIMS): (M+H)⁺490, MP: 58-65° C.

[0241] Proceeding as described in example 12 above, but substituting3-(tert-butyldimethyl-silyloxy) propanol with2-(tert-butyldiphenylsilyloxy)ethanol provided3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldiphenylsilyloxy-ethylamino)phenyl]-1H-pyrrole-2,5-dione.

Example 13 Synthesis of3-(1-methylindol-3-yl)-4-[3-(3-hydroxypropylamino)phenyl]-1H-pyrrole-2,5-dione

[0242]

[0243] To a solution of3-(1-methylindol-3-yl)-4-[3-(3-tert-butylsilyloxypropylamino)-phenyl]-1H-pyrrole-2,5-dione (85 mg,0. 17 mmol) in THF (3 mL) was added a solution of 1Mtetrabutylammonium fluoride in THF (5 mL) via a syringe. The reactionmixture was stirred at room temperature for 1 h and then concentrated invacuo. The residue was purified by preparatory TLC (4% MeOH/CH₂Cl₂) togive 3-(1-methylindol-3-yl)-4-[3-hydroxy-propylamino)phenyl]-1H-pyrrole-2,5-dione which was converted to HCl salt ( 29 mg, 41%) by dissolvingit in MeOH and adding 1M HCl in ether (3 mL). MS(LSIMS): (M+H)⁺376, MP:180-192° C.

[0244] Proceeding as described in example 13 above, but substituting3-(1-methylindol-3-yl)-4-[3-(3-tert-butylsilyloxypropylamino)-phenyl]-1H-pyrrole-2,5-dione with3-(1-methylindol-3-yl)-4-[3-(3-tert-butyldiphenylsilyloxyethylamino)phenyl]-1H-pyrrole-2,5-dione provided3-(1-methylindol-3-yl)-4-[3-(2-hydroxyethylamino)phenyl]-1H-pyrrole-2,5-dione.MS(LSIMS): (M+H)⁺362, MP: 170.3-170.6° C.

Example 14 Synthesis of3-(1-methylindol-3-yl)4-[3-(3-hydroxy-1-methylpropylamino)phenyl]-1H-pyrrole-2,5-dione

[0245]

[0246] To a mixture of3-(l-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (0.2 g,0.6 mmol) and 4-hydroxy-2-butanone (80 mg, 1,5 eq) in dichloromethane(15 mL) was added NaCNBH₃ (56 mg, 1.5 eq) and the reaction mixture wasstirred at RT for three days. The product 3-(1-methylindol-3-yl)-4-[3-(3-hydroxy-1-methylpropylamino)phenyl]-1H -pyrrole-2,5-dioneseparated by preparatory TLC (8.9 mg, 3.6%). LC/MS: M⁺389.

Example 15 Synthesis of3-(1-methylindol-3-yl)-4-[3-(2-hydroxy-1-methylethylamino)phenyl]-1H-pyrrole-2,5-dione

[0247]

[0248] To a mixture of3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione (100 mg,0.32 mmol) and hydroxyacetone (0.03 mL, 1.5 eq) in CH₂Cl₂ (12 mL) andTHF (5 mL) was added NaCNBH₃ (28 mg, 1.5 eq) and the reaction mixturewas stirred overnight. The volatiles were removed under vacuo and theresidue was purified by preparatory TLC to give3-(1-methylindol-3-yl)-4-[3-(2-hydroxy-1-methylethylamino)phenyl]-1H-pyrrole-2,5-dione(8 mg). LC/MS: M⁺375(85.6%).

Example 16 Synthesis of3-(1-methyl-5-chloroindol-3-yl)-4-{3-[((RS)-2,3-dihydroxypropylamino]phenyl}-1H-pyrrole-2,5-dione

[0249]

[0250] Step 1

[0251] To room temperature solution of 5-chloroindole (4.97 g) in dryDMF (40 mL) was added potassium hydroxide pellets (2.76 g) and stirred 1h until most of the solid dissolved. The resulting mixture was cooled to0° C. in an ice bath and iodomethane (2.45 mL) was added dropwise andlater stirred overnight at room temperature under argon. The reactionmixture was poured into water and extracted twice with ETOAc. Thecombined ETOAc portions were combined, washed with water, dried overmagnesium sulfate, concentrated, and flash chromatographed with 10%ETOAc/Hexane to give 1-methyl-5-chloroindole as a pink liquid (5.43 g).

[0252] Step 2

[0253] 1-Methyl-5-chloroindole-3-glyoxylyl chloride was prepared byproceeding as described in Example 12, Step 1, but substituting1-methyl-5-chloroindole for 1-methylindole.

[0254] Step 3

[0255] 3-(1-Methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dionewas prepared by proceeding as described in Example 12, Step 2, butsubstituting 1-methyl-5-chloroindole-3-glyoxylyl chloride for1-methylindole-3-glyoxylyl chloride.

[0256] Step 4

[0257]3-(1-Methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 12, Step 3, butsubstituting 3-(l-methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione for3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione.

[0258] Step 5

[0259] A mixture of3-(1-methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione(865 mg), 10% palladium on carbon (90 mg), and glacial HOAc (35 mL) wasstirred and hydrogenated at atmospheric pressure using a balloon (2 h) .The reaction mixture was filtered through a pad of celite, cooled to 0°C. and KOH pellets were added until pH 8. The solution was extractedwith ETOAc, dried (magnesium sulfate), and stripped. The crude was flashchromatographed with 10% through 20% ETOAc-Hexane to provide3-(1-methyl-5-chloroindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione(495 mg).

[0260] Step 6

[0261] To a room temperature solution of3-(1-methyl-5-chloroindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole -2,5-dione(492 mg) in methanol (250 mL) was added DL-glyceraldehyde dimerdissolved in water (15 mL) followed by sodium cyanoborohydride (110 mg)and the reaction mixture was stirred overnight under argon. The reactionappeared to be only 30% complete by TLC. Additional dimer (150 mg) andcyanoborohydride (100 mg) were added. After another 6 h, the reactionappeared to be 50% complete. The solvent was removed and the cruderesidue was flash chromatographed with 5% to 7% to 10%MeOH/dichloromethane.3-(1-Methyl-5-chloroindol-3-yl)-4-{3-[((RS)-2,3-dihydroxpropylamino]phenyl}-1H-pyrrole-2,5-dionewas obtained as a dark red solid (220 mg). MS(EI): (M+H)⁺426. M. pt.224.8-226.1° C.

Example 17 Synthesis of3-(1-methyl-5-fluoroindol-3-yl)-4-{3-[((RS)-2,3-dihydroxy-propylamino]phenyl}-1H-pyrrole-2,5-dione

[0262]

[0263] Step 1

[0264] 1-Methyl-5-fluoroindole was prepared by proceeding as describedin Example 16, Step 1, but substituting 5-fluoroindole for5-chloroindole.

[0265] Step 2

[0266] 1-Methyl-5-fluoroindole-3-glyoxylyl chloride was prepared byproceeding as described in Example 16 , Step 2, but substituting1-methyl-5-fluoroindole for 1-methyl-chloroindole.

[0267] Step 3

[0268] 3-(1-Methyl-5-fluoroindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dionewas prepared by proceeding as described in Example 16, Step 3, butsubstituting 1-methyl-5-fluoroindole-3-glyoxylyl chloride for1-methyl-5-chloroindole-3-glyoxylyl chloride.

[0269] Step 4

[0270]3-(1-Methyl-5-fluoroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 16, Step 3, butsubstituting 3-(1-methyl-5-fluoroindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione for3-(1-methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione.

[0271] Step 5

[0272]3-(1-Methyl-5-fluoroindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 16, Step 5, butsubstituting 3-(1-3-(1-methyl-5-fluoroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione for1-methyl-5-chloroindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole -2,5-dione.

[0273] Step 6

[0274]3-(1-methyl-5-fluoroindol-3-yl)-4-{3-[((RS)-2,3-dihydroxypropylamino]phenyl}-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 16, Step 5, butsubstituting 3-(1-methyl-5-fluoroindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dione for3-(1-methyl-5-chloroindol-3-yl) -4-(3-aminophenyl)-1H-pyrrole-2,5-dione.MS(EI) (M+H)⁺410, MP: 223.2°-225°.

Example 18 Synthesis of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione

[0275]

[0276] Step 1

[0277] To a cold methanol (20 mL) at 0° C. was added thionyl chloride (7mL) dropwise. After the completion of the addition, the reaction mixturewas stirred at 0° C. for 10 min, and was then added3-mercaptophenylacetic acid (4.0 g, 23.8 mmol). The resulting mixturewas stirred at room temperature overnight. Volatiles were removed andthe residue was partitioned between water and ethyl acetate. The organiclayer was separated, washed with H₂O, NaHCO₃, and NaCl (sat.) and driedover Na₂SO₄. The crude product was purified on a silica gel column with20% EtOAc in hexane to give bis(3-ethoxycarbonylmethylphenyl)-disulfide(4.1 g).

[0278] Step2

[0279] To a solution of bis(3-methoxycarbonylmethylphenyl)disulfide (4.1g, 11mmol) in THF (20 mL) and methanol (5 mL) was added NaBH₄(1.76 g, 4eq.) and the resulting mixture was stirred at RT overnight. It was thenquenched with NH₄Cl (sat.) and extracted with EtOAc. The EtOAc layer waswashed with water, NaCl (sat.) and dried over Na₂SO₄. Column purificatonwith 5% EtOAc in hexane gave 3.47 g of methyl (3-mercaptophenyl)acetate(84%).

[0280] Step 3

[0281] To a solution of methyl (3-mercaptophenyl)acetate (3.47 g, 19mmol) in N-methylpyrrolidinone (100 mL) were added(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-tosylate) (6.54 g, 1.2 eq.)and K₂CO₃ (7.9 g, 4 eq.). The reaction mixture was heated at 65° C.overnight. It was cooled to room temperature, quenched with water andextracted with EtOAc. The organic layer was separated, washed with waterand NaCl (sat.), and dried over Na₂SO₄. The crude product was purifiedon a silica gel column with 10% EtOAc in hexane to give 5.2 g of methyl3-(R)-2,2-dimethyl -1,3-dioxolan-4-ylmethylsulfanyl)phenylacetate (92%).

[0282] Step 4

[0283] Oxalyl chloride (1.05 eq., 3.64 mL) was added dropwise to asolution of N-methylindole (5.1 mL, 50 mmol) in diethyl ether (395 mL)at 0° C. Yellow precipitates were formed. After the completion of theaddition, the reaction mixture was stirred at 0° C. for 30 min. Thesuspension was then dropwise added to a solution of 100 mL of ammoniumhydroxide at 0° C. White precipitate was formed and the reaction mixturewas stirred at 0° C. for 10 min., after the completion of addition.Dichloromethane was added to extract and the organic layer wasseparated, washed with NaCl (sat.), dried over sodium sulfate andconcentrated. The residue was recrystallized from dichloromethane andhexane to give 5.6 g of N-methylindolyl-3-glyoxylamide.

[0284] Step 5

[0285] To a solution of N-methylindolyl-3-glyoxylamide (0.404 g, 2 mmol)in THF (15 mL) at 0° C. was added potassium tert-butoxide (2 mL, 1.0 Min THF) dropwise. Precipitate was formed and the reaction mixture wasstirred at 0° C. for 5 min. Methyl3-(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl) phenylacetate (0.65g, 1.1 eq.) was then added, stirred for 5 min., and was followed by theaddition of potassium tert-butoxide (4 mL, 1.0 M). The resulting mixturewas stirred at 0° C. for 2 h and was allowed to warm to rt. After 3 h,methyl 3-(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl) phenylacetate(0.65 g) was added and the reaction mixture was stirred at rt overnight.It was then quenched with ammonium chloride (sat.) and extracted withEtOAc. The organic layer was washed with NaCl (sat.), dried andconcentrated. Column purification with 7/43/50 of EtOAc/CH₂Cl₂/hexanesgave 0.52 g of 3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)-phenyl]-1H-pyrrole-2,5-dione. MS(EI): M⁺448.

Example 19 Synthesis of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfinyl)phenyl]-1H-pyrrole-2,5-dione

[0286]

[0287] To a solution of3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (100 mg, 0.22 mmol) in methanol (5 mL) andwater (2.5 mL) at -10° C. was added oxone (16 mg, 1.15 eq.) and stirredfor 2 h at -10° C. The reaction mixture was then poured into ice waterand extracted with dichloromethane. The organic layer was washed withNaS₂O₃ (15% aq.), NaCl (sat.) and dried over sodium sulfate. PreparativeTLC with 2/4/4 of acetone/dichloromethane/hexane gave 45 mg of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfinyl)phenyl]-1H-pyrrole-2,5-dione. MS (ESI):(M+1)⁺465.

Example 20 Synthesis of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfonyl)phenyl]-1H-pyrrole-2,5-dione

[0288]

[0289] To a solution of3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (100 mg, 0.22 mmol) in methanol (20 mL) andwater (5 mL) was added oxone in 5 mL of water at 0° C. The resultingsuspension was stirred at 0° C. for 30 min., and was allowed to warm tort and stirred for 5 h. The reaction mixture was then poured into icewater and extracted with dichloromethane. The organic layer was washedwith NaS₂O₃ (15% aq.), NaCl (sat.) and dried over sodium sulfate.Preparative TLC with 2/4/4 of acetone/dichloromethane/hexane gave 40 mgof 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfonyl)phenyl]-1H-pyrrole-2,5-dione. MS (ESI): (M+1)⁺481.

Example 21 Synthesis of3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfanyl)phenyl]-1H-pyrrole-2,5-dione

[0290]

[0291] Toluenesulfonic acid (10 mg) was added to a solution of3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dione(60 mg) in methanol (10 mL) and water (1 mL) and the reaction mixturewas heated at 50° C. for 2 h. The volatiles were removed and the residuewas partitioned between water and EtOAc. The organic layer was washedwith NaCl (sat.) and dried over sodium sulfate. The crude product waspurified on a silica gel column with 10/45/45 of MeOH/CH₂Cl₂/hexane andfurther purified by recrystallization from CH₂Cl/hexane to give3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfanyl)phenyl]-1H-pyrrole-2,5-dione (47 mg). MS (EI): M⁺408.

[0292] Following the procedure described above but substituting3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dionewith 3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfinyl)phenyl]-1H-pyrrole-2,5-dionegave3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfinyl)-phenyl]-1H-pyrrole-2,5-dione.MS (ESI): (M+1)⁺425.

[0293] Following the procedure described above but substituting3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfanyl)phenyl]-1H-pyrrole-2,5-dionewith 3-(1-methylindol-3-yl)-4-{3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethylsulfonyl)phenyl]-1H-pyrrole-2,5-dionegave3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropylsulfonyl)-phenyl]-1H-pyrrole-2,5-dione.MS (ESI): (M+1)⁺441.

Example 22 Synthesis of3-{3-[(2,3-dihydroxypropyl)amino]phenyl}-4-[5-fluoro-1-(3-hydroxypropyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione

[0294]

[0295] Step 1

[0296] Chlorotriphenylmethane (14.64 g, 52.5 mmol) was added at once toa solution of 3-bromo-1-propanol (6.95 g, 62.5 mmol) in pyridine (30 mL)under argon. The solution was stirred under argon for 12 hours and aprecipitate formed. It was filtered and washed with pyridine. Thefiltrate was stripped and combined with the previous precipitate. Thissubstance was purified via column chromatography (SiO₂, 5% CH₂Cl₂/Hexanethen 10% CH₂Cl₂/Hexane). The colorless oil (5.2 g) was allowed tosolidify and was recrystallized from hexane to provide the protectedalcohol (5.2 g).

[0297] Step 2

[0298] To a solution of sodium hydride (60%, 0.44 g, 10.9 mmol) indimethylformamide (8 mL) under argon at room temperature was added5-fluoroindole (0.98 g, 7.25 mmol) in dimethylformamide (10 mL). Theresultant solution was stirred for 1 hour and then cooled to 0° C. Thebromide (Step 1- above, 4.15 g, 10.9 mmol) in dimethylformamide (15 mL)was added and the reaction was allowed to come to room temperature andstir for 12 hours. The mixture was poured in water (200 mL) andextracted with ethyl acetate (2X). The organic solution was washed withwater (2X) and dried (brine, MgSO₄). Evaporation under reduced pressureprovided a colorless oil (4.9 g) which was purified throughchromatography (SiO₂, 5% ETOAc-Hexane) yielding the indole as a whitesolid (2.98 g).

[0299] Step 3

[0300] The alkylated fluoroindole (Step 2 —above) was converted to thenitroaryl indole through procedures previously described in Example 7,steps 1-3.

[0301] Step 4

[0302] A suspension of nitroaryl indole (Step 3 —above, 0.7 g, 10.7mmol), triirondodecacarbonyl (0.65 g, 1.3 mmol), and absolute ethanol(30 mL) was refluxed overnight under argon. The hot mixture was filteredthrough a Buchner funnel packed tightly with celite and washed severaltimes with hot methanol and hot 50% MeOH/EtOAc until most of the orangecolor was removed. Evaporation of the volatiles under reduced pressureand purification via chromatography (SiO₂, CH₂Cl₂, then 1% MeOH/CH₂Cl₂,then 2% MeOH/CH₂Cl₂) yielded the aniline as an orange solid (0.43).

[0303] Step 5

[0304] DL-glyceraldehyde(0.25 g, 1.38 mmol) in water (30 mL) was addedto a solution of the aniline (Step 4 - above, 0.43 g, 0.69 mmol) in MeOH(completely dissolved) under argon. The reaction was stirred for 30minutes, sodium cyanoborohydride (89 mg, 1.38 mmol) was added and themixture was stirred for 12 hours. Evaporation under reduced pressure andpurification through chromatography (SiO₂, 5% MeOH/CH₂Cl₂/0.5% NH4OH)provided the diol as an orange foam (295 mg).

[0305] Step 6

[0306] To a room temperature solution of the diol (Step 5 —above, 0.245g, 0.35 mmol) in methylene chloride (10mL) under argon was addedtrifluoroacetic acid (0.16 mL, 2.22 mmol) followed by trifluoroaceticanhydride (0.3 mL, 2.11 mmol). The reaction was stirred for 10 minutes,cooled to 0° C. and triethylamine (0.6 mL) was added. The solution wasstirred for 15 minutes, water (0.5 ml) was added and the reaction waspoured into MeOH (10 mL). Evaporation of the volatiles under reducedpressure yielded a crude reaction residue. This was dissolved inmethylene chloride, washed with brine (5%) and evaporated in vacuo. Theresultant material was dissolved in methylene chloride/methanol (50%)and treated with triethylamine. (1-2 s) and evaporated under reducedpressure. Purification via chromatography (SiO₂, CH₂Cl₂ then 5% MeOH/CH₂Cl₂) provided the free base. Addition of hydrochloric acid in ether(1M, 2 eq.) followed by removal of the volatiles yielded3-{3-[(2,3-dihydroxypropyl)amino]phenyl}-4-[5-fluoro-1-(3-hydroxypropyl)-1H-indol-3-yl]-1H-pyrrole-2,5-dione (94 mg). MP 118-125°: MS(EI): (M+H)⁺454.

Example 23 Synthesis of3-(5-fluoro-1-methyl-1H-indol-3-yl)-4-[3-(4-hydroxypiperidin-1-yl)phenyl]-1H-pyrrole-2,5-dione

[0307]

[0308] Step 1

[0309] To a room temperature solution of 3-bromophenethyl alcoholalcohol (1.22 g, 6.05 mmoles) in methylene chloride (20 mL) anddihydrofuran (2.54 g, 30.3 mmoles) was added p-toluenesulfonic acidmonohydrate (11.5 mg, 0.06 mmoles). The reaction was stirred for 30minutes followed by the addition of ether (50 mL). The organic solutionwas washed with saturated aqueous sodium bicarbonate solution (50 mL),dried (MgSO₄), and evaporated under reduced pressure to an oil (3.5 g).This was purified via flash chromatography (SiO₂, 4% EtOAc /Hexane)providing 2-[2-(3-bromophenyl) ethoxy]tetrahydro-2H-pyran, as acolorless liquid (1.4 g).

[0310] Step 2

[0311] The tetrahydropyran (Step 1—above, 0.40 g, 1.97 mmoles), BINAP(90 mg, 0.295 mmoles), Pd₂(dba)₃ (90 mg, 0.0486 mmoles), anhydroussodium t-butoxide (0.28 g) were suspended in toluene (20 mL) underargon. 4-{[tert-butyl(diphenyl)silyl]oxy}piperidine (0.67 g, 1.97 mmoles) was then added and the reaction was stirred at 100° for 12 hours.After cooling to room temperature, ether (50 mL) was added, the reactionmixture was filtered through celite and washed with additional ether (25mL). Evaporation under reduced pressure and purification throughchromatography (SiO₂, 5% to 7% EtOAc/Hexane) yielded4-{[tert-butyl(diphenyl)silyl]oxy}-1-{3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]phenyl} piperidine as a tan oil (0.674 g, 1.24 mmoles).

[0312] Step 3

[0313] A solution of the piperidine (Step 2 —above, 0.64 g, 1.18 mmoles)in acetic acid/tetrahydrofuran/water (4:2:1) was stirred under argon at50° for 24 hours. After removal of the volatiles via evaporation,toluene was added and the reaction was evaporated a second time.Purification via flash chromatography (SiO₂, 10% EtOAc/Hexane) yieldedthe primary alcohol (0.42 g, 0.914 mmoles).

[0314] Step 4

[0315] To a 0° solution of the alcohol (Step 3 —above, 0.42 g, 0.914mmoles) in acetone (6 mL) was added Jones Reagent (1.9 M, 1.05 mL)dropwise. The solution was stirred at 0° C. for 1 hour, warmed to roomtemperature and allowed to stir for an additional 2 hours. Isopropanol(10 mL) was added dropwise, the reaction was filtered through celite andwashed with acetone (40 mL). The filtrate was evaporated under reducedpressure, water was added and the mixture was extracted with ethylacetate (2X). The organic solution was dried (brine, MgSO₄), andevaporated in vacuo to provide the carboxylic acid as a solid (100 mg,0.21 mmoles).

[0316] Step 5

[0317] To a room temperature solution of the acid (Step 4 —above, 100mg, 0.21 mmoles) in methylene chloride (5 mL) under argon was addedoxalyl chloride (22 μL) dropwise. The reaction was stirred for 2 hours,cooled to 0° and ammonia hydroxide (0.5 mL) was added dropwise. Themixture was stirred at room temperature for 1 hour and evaporated underreduced pressure. The crude mixture was dissolved in methylene chloride,filtered and evaporated in vacuo to yield the amide (94.5 mg, 0.2mmoles).

[0318] Step 6

[0319] To a 0° C. solution of 1-methylindole (7.58 g, 50 mmoles) in dryether (75 mL) under argon was added oxalyl chloride (4.36 mL, 50 mmoles)slowly. The resulting suspension was stirred for 30 minutes. Aftercooling to −65° C., sodium methoxide (22.9 mL, 100 mmoles, 25% in MeOH)was added dropwise at a rate to maintain −60° C. After the addition wascomplete, the reaction was allowed to warm to room temperature and stirfor 2 hours. Water was added (30 mL) and the crude mixture was stirredthen filtered. The resultant solid was washed with water, ether and thenair dried. Purification of the crude product via flash chromatography(SiO₂, 20% to 40% ethyl acetate/Hexane—gradient) provided methyl(1-methyl-1H-indol-3-yl)(oxo)acetate as a solid (9 g, 41.4 mmoles).

[0320] Step 7

[0321] To a 0° C. of methyl (1-methyl-1H-indol-3-yl)(oxo)acetate (Step 6—above, 51.3 mg, 0.237 mmoles) and2-[3-(4-{[tert-butyl(diphenyl)silyl]oxy}piperidin-1-yl)phenyl]acetamide(Step 5 —above, 93.3 mg, 0.197 mmoles) in tetrahydrofuran (10 mL) wasadded dropwise a solution of potassium t-butoxide (0.59 mL, 0.591mmoles, 1M in THF). The reaction was stirred at room temperature for 12hours. Water was added to the suspension and the mixture was extractedwith ether (2X), dried (brine, MgSO4). Evaporation of the volatilesunder reduced pressure and purification via flash chromatography (SiO₂,1% MeOH/CH₂Cl₂) provided the indole (54 mg, 0.084 mmoles).

[0322] Step 8

[0323] To a room temperature solution of the indole (Step 7 —above, 52mg, 0.0812 mmoles) in dry tetrahydrofuran (3 mL) under argon was addedtetrabutlyammonium fluoride (0.122 mL, 0.122 mmoles, 1 M in THF). Thereaction was stirred for 12 hours and then water (25 mL) was added. Themixture was extracted with ethyl acetate (2X), dried (brine, MgSO₄), andevaporated in vacuo. Purification of the resultant product via flashchromatography (SiO₂, 4% MeOH/CH₂Cl₂) provided3-[3-(4-hydroxypiperidin-1-yl)phenyl]-4-(1-methyl-1H-indol-3-yl)-1H-pyrrole-2,5-dioneas a powder (29.9 mg, 0.0745 mmoles). MP 136-141°: MS(EI):(M+H)⁺402.

Example 24

[0324]

[0325] Following the procedure described in examples 1 and 2, butsubstituting N-methylindole with N-methyl -5-chloroindole andN-methyl-5-fluoroindole in step 4 of example 1 gave give3-(1-methyl-5-chloroindol-3-yl)-4-{3-[((R)-2-hydroxy-2-hydroxymethyl)ethyloxy]phenyl}-1H-pyrrole-2,5-dione(MS (EI): (M+H)⁺427); and3-(1-methyl-5-fluoroindol-3-yl)-4-{3-[((R)-2-hydroxy-2-hydroxymethyl)ethyloxy]phenyl}-1H-pyrrole-2,5-dione (MS (EI): (M+H)⁺411);respectively.

Example 25 Synthesis of3-(5-methoxy-1-methylindol-3-yl)-4-{3-[(2,3-dihydroxy-propyl)amino]phenyl}-1H-pyrrole-2,5-dione

[0326]

[0327] Step 1

[0328] A mixture of 5-methoxylindole-2-Carboxylic Acid (6 g, 31.4 mmol)and basic Copper(II) carbonate(0.6 g) was heated to 230° C.-240° C.under N₂ for five to six hours. After cooling, the resulting black gumwas treated with benzene and filtered. The filtrate was concentrated andpurified by flash column with 9/1 Hex/EtOAc then with 6/1 Hexane/EtOAc.The desired product, 5-methoxyindole (3.1 g) was obtained (61.6%). MS(EI): (M⁺+1) 148.

[0329] Step 2

[0330] To a solution of 5-methoxyindole (1 g, 6.8 mmol) in 8 mL of DMFwere added potassium hydroxide (0.92 g, 2.4 eq.) and methyl iodide (1mL, 16 mmol). The resulting mixture was stirred at room temperatureovernight. After removing volatile, the residue was diluted with EtOAcand washed with water (4 ×). The organic layer was dried andconcentrated to afford 0.9 g (82%) 5-methoxyl -1-methylindole. MS (EI):(M⁺+1) 162.

[0331] Step 3

[0332] 3-(5-methoxy-1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dionewas prepared by proceeding as described in Example 7, step 1 and 2, butsubstituting 5-methoxy-1-methylindole for 1-methylindole.

[0333] Step 4

[0334]3-(5-methoxy-1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 7, step 3, butsubstituting 3-(5-methoxy-1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione for3-(1-methylindol-3-yl)-4-(3-nitrophenyl)furan-2,5-dione.

[0335] Step 5

[0336]3-(5-methoxy-1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole-2,5-dionewas prepared by proceeding as described in Example 7, step 4, butsubstituting 3-(5-methoxy-1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione for3-(1-methylindol-3-yl)-4-(3-nitrophenyl)-1H-pyrrole-2,5-dione.

[0337] Step 6

[0338]3-(5-methoxy-1-methyl-1H-indol-3-yl)-4-{3-[(2,3-dihydroxy-propyl)amino]phenyl}-1H-pyrrole-2,5-dionewas prepared as described in Example 7, step 5, but substituting3-(5-methoxy-1-methylindol-3-yl) -4-(3-aminophenyl)-1H-pyrrole-2,5-dionefor 3-(1-methylindol-3-yl)-4-(3-aminophenyl)-1H-pyrrole -2,5-dione. MS(EI): M⁺421

[0339] Following the procedure described above, but substituting5-methylindole-2-carboxylic acid for 5-methoxylindole -2-carboxylic Acidin step 1 afforded3-(1,5-dimethyl-1H-indol-3-yl)-4-{3-[(2,3-dihydroxy-propyl) amino]phenyl}-1H-pyrrole-2,5-dione. MS (EI): M⁺405.

Example 26 Synthesis of3-(5-isopropoxy-1-methylindol-3-yl)-4-{3-[(2,3-dihydroxy-propyl)amino]phenyl}-1H-pyrrole-2,5-dione

[0340]

[0341] Step 1

[0342] A mixture of 3-methyl-4-nitrophenol (4.59 g, 0.03 mol) and2-bromopropane (4.06 g, 0.033 mol) was refluxed with potassium carbonate(10 g) in acetone (200 mL) for 5 hours. After cooling, the reactionmixture was filtered through celite and the residue was purified byflash column (9/1 of Hexane/EtOAc) to afford 3.42 g of4-isopropoxy-2-methyl-1-nitrobenzene (58.5%).

[0343] Step 2

[0344] A mixture of 4-isopropoxy-2-methyl-1-nitrobenzene (3.55 g,0.018mol) and tert-butoxybis (dimethylamino)methane (9 mL) was refluxed for 4hours and the volatile was removed. The dark brown residue was dissolvedin THF (150 mL) and hydrogenated with catalytic amount of 10% Pd onCarbon with H₂ in aballoon. After stirring at room temperatureovernight, the catalyst was filtered off and the filtrate wasconcentrated to afford 3.07 g 5-isopropoxyindole (96%). MS(EI): (M⁺+1)176.

[0345] Step 3

[0346] Procedure described in Example 24, step 2 through step 6 wasfollowed, but substituting 5-isopropoxyindole for 5-methoxyindole toprovide3-(5-isopropoxy-1-methyl-indol-3-yl)-4-{3-[(2,3-dihydroxy-propyl)amino]phenyl}-1H-pyrrole-2,5-dione. MS (EI): M⁺449.

Example 27 Synthesis of3-(1-methyl-indol-3-yl)-4-{3-((R)-2,3-dihydroxy-propoxyl)-2-methylphenyl}-1H-pyrrole-2,5-dione

[0347]

[0348] Step 1

[0349] To a methanol solution (25 mL) at 0° C. was dropwise addedthionyl chloride (9.6 mL, 0.13 mol). After 15 minutes,3-hydroxy-2-methylbenzoic acid (4 g, 0.033 mol) was added and theresulting mixture was stirred at room temperature for 24 hours. Volatilewas removed under vacuo and the residue was partitioned between waterand ethyl acetate. The organic layer was separated, washed with waterand saturated sodium chloride solution, and was dried over sodiumsulfate. After concentration, the crude product was recrystallized fromdichloromethane and hexane to gave 3.48 g of methyl3-hydroxy-2-methylbenzoate.

[0350] Step 2

[0351] To a solution of methyl 3-hydroxy-2-methylbenzoate (3.0 g, 18mmol) in N-methylpyrrolidinone (30 mL) was added(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-tosylate (6.2 g, 1.2 eq.),and followed by K₂CO₃ (7.5 g, 3 eq.). After the mixture was heated at96° C. overnight, it was cooled to room temperature, quenched with H₂O,and partitioned between H₂O and EtOAc. The organic layer was separated,washed with H₂0 and NaCl (sat.), and then dried over Na₂SO₄. The crudeproduct was purified on a silica gel column with 20% EtOAc in hexane togive methyl3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-methylbenzoate as anoil (4.5 g).

[0352] Step 3

[0353] Methyl3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-methylbenzoate (4.2 g,15 mmol) was dissolved in 20 mL of methanol and 1 mL of water. To theabove solution was added lithium hydroxide (2.4 g, Seq.). After stirringthe reaction mixture at room temperature for 4 h, the volatile wasremoved under vacuo and the residue was partitioned between EtOAc andH₂O. The aqueous layer was separated, cooled with an ice bath, and thenacidified with 10% aq. HCl. The acidic aqueous layer was extracted withEtOAc. The EtOAc layer was washed with NaCl (sat.), dried over Na₂SO₄,and concentrated to give3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)benzoic acid as a whitesolid (4 g).

[0354] Step 4

[0355] To a solution of3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-methylbenzoic acid(2.4 g, 9 mmol) in 20 mL of dichloromethane was added oxalyl chloride(0.86 mL, 1.1 eq.). The resulting mixture was stirred at roomtemperature in the presence of a catalytic amount of DMF. Bubbles formedand stirring continued until no more bubbles were generated. Volatilewas removed under vacuo and the residue was suspended in ether (20 mL)and was added dropwise to an ether solution (60 mL) at 0° C. containingdiazomethane generated from N-nitroso-N-methylurea (6.95 g, 7.5 eg.) and19 g of potassium hydroxide according to the procedure described byBerkowitz, D. B. in J. Org. Chem. 65, 847, (2000). The resulting mixturewas stirred at 0° C. for 1h and was allowed to warm to room temperature,where it was stirred for another hour. Excess amount of diazomethane wasquenched with acetic acid and the volatile was removed under vacuo. Theresidue was purified on a silica gel column with 10% ethyl acetate inhexane to give 0.8 g of2-diazo-1-[3-((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-methyl-phenyl]ethanone.

[0356] Step 5

[0357] To a solution of2-diazo-1-[3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-methyl-phenyl]ethanone(0.5 g, 1.73 mmol) in 20 mL of methanol at room temperature was addeddropwise a solution of silver benzoate (52 mg, 13%) in 2.6 mL oftriethylamine. The solution turned greenish and then brown, blackprecipitate formed. After stirring for 1.5 h, it was filtered throughcelite and the filtrate was concentrated. The residue was then purifiedon a silica gel column with 20% ethyl acetate in hexane to afford 0.43 gof [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl]acetic acid methyl ester. The above ester was then hydrolyzed bystirring with lithium hydroxide (0.25 g) in 5 mL of methanol at roomtemperature to give 0.4 g of[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl] aceticacid.

[0358] Step 6

[0359]3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl]furan-2,5-dionewas prepared according to the procedure described in Example 1, step 4,but substituting[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl] aceticacid for 3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenylaceticacid.

[0360] Step 7

[0361]3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl]-1H-pyrrole-2,5-dione was prepared according to the procedure described inExample 1, step 5, but substituting3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy))-2-methylphenyl]furan-2,5-dionefor3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]furan-2,5-dione.

[0362] Step 8

[0363]3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropoxy)-2-methylphenyl]-1H-pyrrole-2,5-dionewas according to the procedure described in Example 2, step 1, butsubstituting 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-methylphenyl]-1H-pyrrole-2,5-dionefor3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]-1H-pyrrole-2,5-dione. MS (EI): (M⁺+1) 407.

Example 28 Synthesis of3-(1-methyl-indol-3-yl)-4-{3-((R)-2,3-dihydroxy-propoxyl)-2-nitrophenyl}-1H-pyrrole-2,5-dione

[0364]

[0365] Step 1

[0366] To a methanol solution (15 mL) at 0° C. was dropwise addedthionyl chloride (6.4 mL, 0.088 mol). After 15 minutes,3-hydroxy-2-nitrobenzoic acid (4 g, 0.022 mol) was added and theresulting mixture was stirred at room temperature for 72 hours. Volatilewas removed under vacuo and the residue was partitioned between waterand ethyl acetate. The organic layer was separated, washed with waterand saturated sodium chloride, and was dried over sodium sulfate. Afterconcentration, the crude product was recrystallized from dichloromethaneand hexane to gave 4.5g of methyl 3-hydroxy -2-nitrobenzoate.

[0367] Step 2

[0368] To a solution of methyl 3-hydroxy-2-nitrobenzoate (1.97 g, 10mmol) in N-methylpyrrolidinone (15 mL) was added(R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyl p-tosylate (3.43 g, 1.2 eq.),and followed by K₂CO₃ (4.2 g, 3eq.). After the mixture was heated at 96°C. overnight, it was cooled to room temperature, quenched with H₂O, andpartitioned between H₂O and EtOAc. The organic layer was separated,washed with H₂O and NaCl (sat.), and then dried over Na₂SO₄. The crudeproduct was purified on a silica gel column with 20% EtOAc in hexane togive methyl3-((R)-2,2-dimethyl-1,3-dioxolan4-ylmethyloxy)-2-nitrobenzoate as an oil(3.1 g).

[0369] Step 3

[0370] Methyl3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoate (2.8 g,9 mmol) was dissolved in 25 mL of methanol and 2 mL of water. To theabove solution was added lithium hydroxide (1.13 g, 3 eq.). Afterstirring the reaction mixture at room temperature for 5 h, the volatilewas removed under vacuo and the residue was partitioned between EtOAcand H₂O. The aqueous layer was separated, cooled with an ice bath, andthen acidified with 10% aq. HCl. The acidic aqueous layer was extractedwith EtOAc. The EtOAc layer was washed with NaCl (sat.), dried overNa₂SO₄, and concentrated to give3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoic acid as awhite solid (1.9 g).

[0371] Step 4

[0372] To a solution of3-((R)-2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy)-2-nitrobenzoic acid (1.9g, 6.4 mmol) in 20 mL of dichloromethane was added oxalyl chloride (0.55mL, 1.1 eq.). The resulting suspension was stirred at room temperaturein the presence of catalytic amount of DMF. Bubbles formed, and stirringcontinued until no more bubbles were generated while the suspensionturned into a solution. Volatile was removed under vacuo and the residuewas suspended in ether (15 mL) and was added dropwise to an ethersolution (40 mL) at 0° C. containing diazomethane generated fromN-nitroso -N-methylurea (4.95 g, 7.5 eg.) and 13.5 g of potassiumhydroxide according to the procedure described by Berkowitz, D. B. in J.Org. Chem. 65, 847, (2000). The resulting mixture was stirred at 0° C.for 1h and was allowed to warm to room temperature, where it was stirredovernight. Excess of diazomethane was quenched with acetic acid and thevolatile was removed under vacuo. The residue was purified on a silicagel column with 2/4/4 of acetone/dichloromethane/hexane to give 0.95 gof2-diazo-1-[3-((R)-2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-nitrophenyl]ethanone.

[0373] Step 5

[0374] To a solution of2-diazo-1-[3-(2,2-dimethyl-[1,3]-dioxolan-4-ylmethoxy)-2-nitrophenyl]ethanone(0.9 g, 2.8 mmol) in 30 mL of methanol at room temperature was addeddropwise a solution of silver benzoate (84 mg, 13%) in 4.2 mL oftriethylamine. The solution turned greenish and then brown, blackprecipitate formed. After stirring for 1.5 h, it was filtered throughcelite and the filtrate was concentrated. The residue was then purifiedon a silica gel column with 20% ethyl acetate in hexane to afford 0.75 gof [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl]aceticacid methyl ester. The above ester (0.52 g, 1.6 mmol) was thenhydrolyzed by stirring with lithium hydroxide (0.27 g) in 5 mL ofmethanol at room temperature to give 0.5 g of [3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl] acetic acid.

[0375] Step 6

[0376]3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl]furan-2,5-dionewas prepared according to the procedure described in Example 1, step 4,but substituting[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl] aceticacid for 3-((R) -2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenylaceticacid.

[0377] Step 7

[0378] 3-(1-methylindol-3-yl)-4-[3-(R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl]-1H-pyrrole -2,5-dione wasprepared according to the procedure described in Example 1, step 5, butsubstituting3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy))-2-nitrophenyl]furan-2,5-dionefor3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]furan-2,5-dione.

[0379] Step 8

[0380]3-(1-methylindol-3-yl)-4-[3-((R)-2,3-dihydroxypropoxy)-2-nitrophenyl]-1H-pyrrole-2,5-dionewas according to the procedure described in Example 2, step 1, butsubstituting 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)-2-nitrophenyl]-1H-pyrrole-2,5-dionefor 3-(1-methylindol-3-yl)-4-[3-((R)-2,2-dimethyl-[1,3]dioxolan-4-ylmethoxy)phenyl]-1H-pyrrole-2,5-dione.MS (EI): (M⁺+1) 438.

[0381] Following the procedure described above, but substituting5-hydroxy-2-nitrobenzoic acid for 3-hydroxy-2-nitrobenzoic acid gave3-(1-methylindol-3-yl)-4-{5-((R)-2,3-dihydroxy-propoxyl)-2-nitrophenyl}-1H-pyrrole-2,5-dione.MS (EI): (M⁺+1) 438.

Formulation Examples

[0382] The following are representative pharmaceutical formulationscontaining a compound of Formula (I).

Example 1 Tablet formulation

[0383] The following ingredients are mixed intimately and pressed intosingle scored tablets. Quantity per Ingredient tablet, mg compound ofthis invention 400 cornstarch 50 croscarmellose sodium 25 lactose 120magnesium stearate 5

Example 2 Capsule formulation

[0384] The following ingredients are mixed intimately and loaded into ahard-shell gelatin capsule. Quantity per Ingredient capsule, mg compoundof this invention 200 lactose, spray-dried 148 magnesium stearate 2

Example 3 Suspension formulation

[0385] The following ingredients are mixed to form a suspension for oraladministration. Ingredient Amount compound of this invention 1.0 gfumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propylparaben 0.05 g granulated sugar 25.0 g sorbitol (70% solution) 13.00 gVeegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 mL colorings 0.5 mgdistilled water q.s. to 100 mL

Example 4 Injectable formulation

[0386] The following ingredients are mixed to form an injectableformulation. Ingredient Amount compound of this invention 0.2 mg-20 mgsodium acetate buffer solution, 0.4 M 2.0 mL HCl (1N) or NaOH (1N) q.s.to suitable pH water (distilled, sterile) q.s. to 20 mL

Example 5 Suppository formulation

[0387] A suppository of total weight 2.5 g is prepared by mixing thecompound of the invention with Witepsol® H-15 (triglycerides ofsaturated vegetable fatty acid; Riches-Nelson, Inc., N.Y.), and has thefollowing composition: compound of the invention 500 mg Witepsol ® H-15balance

Biological Examples Example 1 Inhibition of Glycogen Synthase Kinase-3β—in vitro assay

[0388] The in vitro GSK-3β inhibitory activity of compounds of thisinvention was determined with a truncated form of recombinant rabbitGSK-3β enzyme.

[0389] Isolation of GSK-3β

[0390] The construct was cloned in pGEX-3X vector according to theprocedure described in Wang, Q. M. et al., J. Biol. Chem. 269,14566-14574 (1994). Ten amino acids at the N-terminus were deleted toobtain constitutively active GSK-3β ((see Murai H. et al., FEBS Lett.392,153-60, (1996)). GSK-3β was expressed in BL21 DE3 cells. The cellswere grown at 37° C. until they reached rnid log phase and then inducedwith isopropyl-beta-(D)-thiogalactopyranoside (final concentration 0.4mM) at 30° C. for 2 h. The cells were homogenized and the cell extractwas loaded on a glutathione sepharose 4B column. GSK-3β was eluted withglutathione buffer (50 mM Tris pH 8 and 10 M reduced glutathione). Theeluate was collected in 3 minute fractions and assayed for GSK-3βcontent on a 10% SDS PAGE (polyacrylamide gel electrophoresis).Fractions above 20% peak height were pooled, aliquoted, and stored at−80° C. until used.

[0391] Inhibition of GSK-3β

[0392] The GSK-3β binding assay was performed in 50 μl reactions in a 96well polypropylene plate, each reaction containing 20 mM magnesiumchloride, 40 μM ATP, 2 mM DTT, 88.5 μM biotinylated and phosphorylatedCREB-peptide substrate (biotin-KRREILSRRPS(PO₄)YR—OH, see Wang, Q. M. etal., J. Biol. Chem. 269, 14566-14574 (1994)), [γ³³P] ATP (1 μCi), and 2μl of compounds of this invention in DMSO (various concentrations). 15μl of GSK-3β (various concentrations) was added and the reaction mixturewas incubated at 30° C. for 1 h. The reaction was stopped bytransferring 25 μl of the reaction mixture to a phosphocellulose platecontaining 130 μl of 1.85% phosphoric acid. The free radionucleotides inthe membrane were washed off under vacuum with 1.85% phosphoric acid (5times). After the last wash, the plate was transferred to an adoptorplate and 50 μl of scintillation cocktail (Microscint-20, Packard, cat.#20-133) was added to each well and the amount of radioactivity wascounted in a top counter.

[0393] Compounds of this invention were active in this assay.

[0394] The GSK-3β inhibitory activities (expressed as IC₅₀, theinhibitor concentration causing 50% inhibition of the activity in thecontrol) of some compounds of the invention disclosed in Table I-IV wereless than 2 μm. Activities of certain specific compounds are shown belowCompound IC₅₀ μM I-1 0.194 II-1 0.02 II-2 0.0264 II-4 0.0296 III-3 0.23IV-1 0.1334

Example 2 Inhibition of β-catenin degradation—in vitro assay

[0395] The cell based GSK-3β activity of compounds of this invention wasdetermined by measuring β-catenin levels in Jurkat T-cells aftertreatment with the compounds of this invention using ELISA as follows.

[0396] Jurkat cells (5×105 cells/mL) were plated in 6-well plates (6mL/well) and then treated with various concentrations of the compoundsof this invention (preferrably 1 nM-10 μM) for 24 h. At the end of theincubation, the cells were collected and washed once with PBS. The cellswere then suspended in 0.3 mL RadioImmuno Precipitation Assay lysis(RIPA) buffer (Boehringer Mannheim, cat.# 1 920 693). After 3freeze—thaw cycles, the cell extracts were centrifuged at 15,000 rpm for10 min. The supernatant was collected and analyzed using ELISA assay asdescribed below.

[0397] 96 Microwell plates were coated overnight with capture antibody(mouse monoclonal anti-β-catenin, Zymed La., cat.# 13-8400, 100 μl perwell, containing 250 ng antibody) diluted in coating buffer (0.1 MNaHCO₃, pH 9.5). The wells were aspirated and washed 3 times with 300 μlof wash buffer (PBS containing 0.05% Tween 20) and blocked with 200 μlof assay diluent (PBS, 10% RBS, pH 7; PharMingen) and then incubated atroom temperature for at least 72 h. The wells were washed again asdescribed above. 100 μl of the Jurkat cell supernatant and variousconcentrations of a β-catenin standard (Behrens et al. Nature, Vol. 382,p638 (1996)) were added to the wells and incubated for 2 h at roomtemperature. After incubation, the wells were washed and 100 μl ofanti-β- catenin antibody (Santa Cruz, β-catenin H-102, sc-7199, rabbitIgG) diluted in assay diluent (1:1250) was added to each well and thecells were incubated at room temperature for 2 h. After washing, 100 μlof working detector (Sigma B5283, mouse monoclonal anti-rabbitIgG-Biotin) diluted in assay diluent (1:2000) was added into each welland incubated for 1 h at room temperature.3,3′,5,5′-Tetramethylbenzidine (PharMingen, Cat. # 2642KK) was used forcolor development. The reaction was stopped by adding 50 μl of stopsolution (2N H₂SO₄) to each well. The plates were read with an ELISAplate reader at 570 nm within 30 min., of stopping the reaction.

[0398] The level of GSK-3β inhibition was calculated by plotting thecompound concentration versus β-catenin levels. The results are shown inFIG. 1, confining the effect of compounds of this invention on β-cateninlevels.

Example 3 Cytokine Secretion Assays—human T-cell assay

[0399] The effect of compounds of this invention on cytokine secretionlevels from human CD4+ T-helper cells was determined as in Rogge et.al., J. Exp. Med. 185, 825-831 (1997).

[0400] For this assay, human neonatal leukocytes were isolated fromfreshly collected, heparinized neonatal blood by Ficoll-Paque (PharmaciaBiotech, Uppsala, Sweden) density gradient centrifugation. To generateTh1 and Th2 cell lines, CD8+ T cells were removed by positive selectionwith anti-CD8 microbeads and magnetic activated cell sorting accordingto a protocol supplied by the manufacturer (Miltenyi Biotec, BergischGladbach, Germany). On day 0, cells were pre-incubated with variousconcentrations of test compound for one day. The next day, cells werestimulated with 2 μL phytohemagglutinin (Wellcome, Beckenham, U.K.) inthe presence of 2.5 ng/mL IL-12 (Hoffmann-La Roche, Nutley, N.J.) and200 ng/mL neutralizing anti-IL-4 antibody (no. 18500D; PharMingen, SanDiego, Calif.) for Th1 cultures or 1 ng/mL IL4 (PharMingen) and 2 μg/mLneutralizing anti-IL-12 antibody 17F7 and 20C2 (kindly provided by M.Gately, Hoffmann-LaRoche) for Th2 cultures, respectively. The cells werewashed on day 3 and expanded in complete RPMI 1640 medium (LifeTechnologies, Milan, Italy), supplemented with compounds of thisinvention, 5% FetalClone I (HyClone, Logan, Utah), 2 mM L-glutamine, 1mM sodium pyruvate, 100 U/mL penicillin-streptomycin, and containing 100U/mL IL-2 (Hoffmann-La Roche). The cells were washed again on day 14 and10⁵ cells were re-stimulated in 96-well round-bottom plates for 24 hwith plate-bound anti-CD3 and anti-CD28 monoclonal antibodies (cloneTR66; see Lanzavecchia, A., and D. Scheidegger., Eur. J. Immunol.17:105-111 (1987)) to measure IFN-gamma, IL-4, and IL-13 in culturesupernatants by ELISA assays (Gallati, H., I. et al ., J. Biol. Regul.Homeostatic Agents. 1:109-118, (1987)). The ED₅₀ values (concentrationof compound that inhibits cytokine secretion to 50% of the maximalvalue) were determined by fitting a sigmoidal curve to the plotted data.

[0401] Compounds of this invention were active in this assay and showedsuppression of IL4, and IL-13 secretion levels, while Interferon-gammalevels remained unchanged.

Example 4 Cytokine Secretion Assays—murine T-cell assay

[0402] CD4+, CD62Lhi cells (naïve T-cells) are isolated from the spleensof Balb/C Do11.10 OA-TCR transgenic mice (Murphy K. M. et al., Science,250, 1720 (1990)) by Ficoll density gradient and Miltenyi magneticimmunobead separations. These naïve T-cells were grown in co-culturewith irradiated Balb/C splenocytes (T:APC of 1:25) under neutralconditions (without the addition of differentiating cytokines). T-cellsare stimulated with 300 nM ovalbumin peptide(NH2-KISQAVHAAHAEINEAG-COOH) in the presence of different inhibitorconcentrations (test compound), including controls with solvent only. Atday 3 the cells were split 1:3, with inhibitors were added back to themedium to maintain the original concentration. On day 6, the cells werecounted, washed, re-plated at a 1:25 ratio with irradiated Balb/Csplenocytes, and re-stimulated with 300 nM ovalbumin peptide. On day 8,the supernatants were harvested and levels of IFN-gamma, IL-4, IL-5, andIL-13 were quantitated by ELISA (R&D Systems). The ED₅₀ values(concentration of compound that inhibits cytokine secretion to 50% ofthe maximal value) were determined by fitting a sigmoidal curve to theplotted data.

[0403] Compounds of this invention were active in this assay and led toa reduction in Th2 cytokine levels.

Example 5 Inhibition of Eosinophil influx into the lungs of Ovalbuminsensitized brown Norway rats—in vivo assay

[0404] The ability of the compounds of the invention to inhibitleukocyte infiltration into the lungs was determined by measuring theinhibition of eosinophil accumulation into the bronchioalveolar lavage(BAL) fluid of Ovalbumin (OA) sensitized brown Norway rats after antigenchallenge by aerosol. Briefly, male brown-Norway rats were sensitizedi.p. with 100 μg of OA in 0.2 mL alum on Day 0, Day 7, and Day 14. OnDay 21, the rats were challenged with 1% OA for 45 min., and sacrificed72 h later. Test compounds or only vehicle (control group) wereadministered from the day before the third immunization until the end ofthe study. At the time of sacrifice, rats were anesthetized (urethane,approx. 2 g/kg, i.p.) and the lungs were lavaged with 3×3 mL BAL. TheBAL fluid was analyzed for total leukocyte number and differentialleukocyte counts. The total leukocyte number in an aliquot of the cells(20 μl) was determined by Coulter Counter. For differential leukocytecounts, 50-200 μl of the samples were centrifuged in a Cytospin and theslide stained with Diff-Quik. The proportions of monocytes, eosinophils,neutrophils and lymphocytes were counted under light microscopy usingstandard morphological criteria and expressed as a percentage.

[0405] Compounds of this invention were active in this assay and led toa reduction in monocytes, eosinophils, neutrophils and lymphocytesinfiltration into the lungs.

Example 6 Reduction of total Serum IgE and Ovalbumin specific IgE inOvalbumin sensitized A/J mice—in vivo assay

[0406] This protocol was designed to examine the effect of compounds onIgE levels in the serum of Ovalbumin (OA) sensitized A/J mice. Theprimary endpoint was IgE production during sensitization. Briefly, maleA/J mice (20-25 g) were sensitized by intraperitoneal injection ofOA/Alum (10 μg in 0.2 mL Al(OH)₃; 2%) on Day 0, and Day 7. On Day 14,the mice were anesthetized with urethane and blood was drawn by cardiacpuncture. Test compounds or only vehicle (control group) wereadministered from the day before the second OA/Alum injection until theend of the study. Total serum IgE and OA-specific IgE were measured byELISA (Pharmingen, cat#2655KI, biotinylated ovalbumin for OA specificIgE) and compared between compound and vehicle treated groups.

[0407] Compounds of this invention were active in this assay and led toa reduction in IgE levels into the lungs.

Example 7 Differential Expression of TCF7 in Th1and Th2 cells

[0408] CD4+, naïve T-cells were prepared as described in Example 4 fromBalb/C Do 11.10 OA-TCR (+/+) transgenic mice and B10.D2 DO11.10OA-TCR(+/−) transgenic mice (Guler M. L. et al., J. Immunol. 162,1339-1347, 1999). Cells were harvested at day 5 after initialstimulation with 300 nM ovalbumin peptide and mRNA was prepared (totalRNA: Chomzynski and Sacchi, Anal. Biochem 162: 150-159, 1987, mRNA:Promega polyA tract) for expression analysis by Northern Blot. Ashybridization probe clone AA119960 (Genbank) was labeled by randompriming (GIBCO 18187-013) (FIG. 2A). As shown in FIG. 2A, expression ofTCF7 transcripts was detected in mRNA from the B10.D2 preparation (Th-1cells) while TCF7 transcripts were undetectable in the mRNA preparationfrom Balb/C T-cells (Th-2 cells). In a separate experiment, CD4+ naïveT-cells from Balb/C Do11.10 OA-TCR (+/+) transgenic mice were eitherstimulated with 300 nM ovalbumin peptide and interferon-gamma orovalbumin peptide for 5 days. mRNA was isolated and used in aquantitative RT-PCR (Baranzini et al., Journal of Immunology. 165:6576-6582, 2000) to determine relative levels of TCF7-mRNA betweenovalbumin induced samples from Balb/C and B10.D2 and relative levels ofovalbumin treated Balb/C samples vs. ovalbumin and IFN-G treated samplesfrom Balb/C CD4+ T-cells. TCF7 primers for the quantitative RT-PCR were:AGCTGCAGCCATATGATAGAA and CTTGAGTGTGCACTCAGCAA. Thus, as shown in FIG.2B, interferon gamma, a cytokine that promotes Th1 differentiation ofBalb/c T-cells, induces the expression of TCF7. Both these experimentsconfirm that TCF7 levels are linked to the T-helper response. Highlevels of TCF7 expression appeared to be linked to a Th1 response, whilelow levels are linked to a Th2 response.

[0409] The foregoing invention has been described in some detail by wayof illustration and example, for purposes of clarity and understanding.It will be obvious to one of skill in the art that changes andmodifications may be practiced within the scope of the appended claims.Therefore, it is to be understood that the above description is intendedto be illustrative and not restrictive. The scope of the inventionshould, therefore, be determined not with reference to the abovedescription, but should instead be determined with reference to thefollowing appended claims, along with the full scope of equivalents towhich such claims are entitled.

[0410] All patents, patent applications and publications cited in thisapplication are hereby incorporated by reference in their entirety forall purposes to the same extent as if each individual patent, patentapplication or publication were so individually denoted.

What is claimed:
 1. A compound represented by Formula (I):

wherein: R¹ and R² independently represent hydrogen, alkyl, halo,haloalkyl, alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino,monoalkylamino, or dialkylamino; R³ represents hydrogen, alkyl,cycloalkyl, heteroalkyl, —COR⁷ (wherein R⁷ is hydrogen or alkyl), orphenyl optionally substituted with one or two substituents independentlyselected from the group consisting of hydrogen, alkyl, haloalkyl,alkylthio, hydroxy, alkoxy, cyano, nitro, amino, acylamino,monoalkylamino, and dialkylamino; R⁴ and R⁵ independently representhydrogen, alkyl, halo, haloalkyl, alkylthio, hydroxy, alkoxy, cyano,nitro, amino, acylamino, monoalkylamino, or dialkylamino; R⁶ isheteroalkyl, heterocyclyl, heterocyclylalkyl, heteroalkylsubstitutedheterocyclyl, heteroalkylsubstituted cycloalkyl, hetereosubstitutedcycloalkyl, —OR⁸, —S(O)_(n)R⁸ (wherein n is 0 to 2; and R⁸ isheteroalkyl, heteroaralkyl, heterocyclyl, or heterocyclylalkyl), —NR⁹R¹⁰(wherein R⁹ is hydrogen or alkyl and R¹⁰ is heteroalkyl, heteroaralkyl,heterosubstituted cycloalkyl, heterocyclyl, or heterocyclylalkyl), or-X-(alkylene)—Y-Z (wherein X is a covalent bond, —O—, —NH—, or—S(O)_(n1−) where n1 is 0 to 2, and Y is —O—, —NH—, or —S—, and Z isheteroalkyl or SiR¹¹R¹²R¹³ where R¹¹, R¹² and R¹³ are independentlyhydrogen or alkyl), or R⁶ together with R⁴ forms a methylenedioxy orethylenedioxy group when they are adjacent to each other; or apharmaceutically acceptable salt thereof.
 2. The compound of claim 1wherein R³ is alkyl.
 3. The compound of claim 2 wherein R³ is methyl. 4.The compound of claim 1 wherein R⁶ group is at the 3-position of thephenyl ring and is heteroalkyl, heterocyclylalkyl, —OR⁸ (wherein R⁸ isheteroalkyl or heterocyclylalkyl), —NHR¹⁰ (wherein R¹⁰ is heteroalkyl,heterosubstituted cycloalkyl, heterocyclyl, or heterocyclylalkyl), or—X-(alkylene) -Y-heteroalkyl (wherein X is a covalent bond, —O— or —NH—and Y is —O— or —NH).
 5. The compound of claim 4 wherein R⁶ is (RS), (R)or (S) 2-hydroxy-2-hydroxymethyl-ethyloxy, 3-hydroxypropyloxy,2-aminoethyloxy, 3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (RS),(-R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy.
 6. The compound ofclaim 4 wherein R⁶ is (RS), (R) or (S)2-hydroxy-2-hydroxymethylethylamino, 2-hydroxyethylamino,3-hydroxypropylamino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 2-hydroxy-1-hydroxymethylethylamino,3-hydroxybutylamino, or tetrahydropyran-4-ylamino.
 7. The compound ofclaim 1 wherein R¹ and R² are hydrogen; R⁴ and R⁵ are at the 2 and the 6positions of the phenyl ring and are independently of each otherhydrogen or halogen; and R⁶ is at the 3-position of the phenyl ring. 8.The compound of claim 7 wherein R³ is alkyl or hydrogen, , R⁶ is —OR⁸(wherein R⁸ is heteroalkyl or heterocyclylalkyl), —NHR¹⁰ (wherein R¹⁰ isheteroalkyl, heterosubstituted cycloalkyl, heterocyclyl, orheterocyclylalkyl), or —X-(alkylene)-Y-heteroalkyl (wherein X is acovalent bond, —O— or —NH— and Y is —O— or —NH).
 9. The compound ofclaim 8 wherein R³ is methyl and R⁴ and R⁵ are independently of eachother hydrogen, chloro, or fluoro.
 10. The compound of claim 9 whereinR⁴ and R⁵ are hydrogen.
 11. The compound of claim 10 wherein R⁶ is (RS),(R) or (S) 2-hydroxy-2-hydroxymethyl-ethyloxy, 3-hydroxypropyloxy,2-aminoethyloxy, 3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (RS),(R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy.
 12. The compound ofclaim 10 wherein R⁶ is (RS), (R) or (S)2-hydroxy-2-hydroxymethylethylamino, 2-hydroxyethylamino,3-hydroxypropylamino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 2-hydroxy-1-hydroxymethylethylamino,3-hydroxybutylamino, or tetrahydropyran-4-ylamino.
 13. The compound ofclaim 1 wherein R¹ is at the 5-position of the indole ring and is halo;R² is hydrogen; R⁴ and R⁵ are at the 2 and the 6 positions of the phenylring and are independently of each other hydrogen or halogen; and R⁶ isat the 3-position of the phenyl ring.
 14. The compound of claim 13wherein R³ is alkyl or hydrogen,, R⁶ is —OR⁸ (wherein R⁸ is heteroalkylor heterocyclylalkyl), —NHR¹⁰ (wherein R¹⁰ is heteroalkyl, heterocyclyl,or heterocyclylalkyl), or -X-(alkylene)-Y-heteroalkyl (wherein X is acovalent bond, —O— or —NH— and Y is —O— or —NH).
 15. The compound ofclaim 14 wherein R¹ is chloro or fluoro; R³ is methyl; and R⁴ and R⁵ areindependently of each other hydrogen, chloro, or fluoro.
 16. Thecompound of claim 15 wherein R⁶ is (RS), (R) or (S)2-hydroxy-2-hydroxymethyl-ethyloxy, 3-hydroxypropyloxy, 2-aminoethyloxy,3-aminopropyloxy, 2-morpholin-4-ylethyloxy, or (RS), (R) or (S)2,2-dimethyl-1,3-dioxolan-4-ylmethyloxy.
 17. The compound of claim 14wherein R⁶ is (RS), (R) or (S) 2-hydroxy-2-hydroxymethylethylamino,2-hydroxyethylamino, 3-hydroxypropylamino, (RS), (R) or (S) 2,2-dimethyl-1,3-dioxolan-4-ylmethylamino, 2-hydroxy-1-hydroxymethylethylamino,3-hydroxybutylamino, or tetrahydropyran-4-ylamino.
 18. A pharmaceuticalcomposition comprising a therapeutically effective amount of a compoundof claim 1 and a pharmaceutically acceptable excipient.
 19. A method oftreating GSK-3β mediated diseases selected from Alzheimer's disease,obesity, diabetes, atherosclerotic cardiovascular disease, polycysticovary syndrome, syndrome X, ischemia, traumatic brain injury, bipolardisorder, immunodeficiency, cancer, allergy, and asthma in a mammalwhich method comprises administration to the mammal a therapeuticallyeffective amount of a compound of claim
 1. 20. The method of claim 19wherein the disease is asthma.
 21. A method of treating a patient havinga disease characterized by an excess of CD4+ Th2 cytokines, comprisingadministering to the patient a therapeutically effective amount of aninhibitor of GSK-3β.
 22. The method of claim 21, wherein the GSK-3βinhibitor is a compound of claim
 1. 23. The method of claim 21, whereinthe disease is asthma, allergy or allergic rhinitis.
 24. The method ofclaim 21, wherein the disease is asthma.
 25. The method of claim 21,wherein the GSK-3β inhibitor is at least 10 fold more selective forGSK-3β relative to PKC.
 26. A method of treating a patient having adisease characterized by an excess IgE production, comprisingadministering to the patient a therapeutically effective amount of aninhibitor of GSK-3β.
 27. The method of claim 26, wherein the GSK-3βinhibitor is a compound of claim
 1. 28. The method of claim 26, whereinthe disease is asthma.
 29. The method of claim 26, wherein the GSK-3βinhibitor is at least 10 fold more selective for GSK-3β relative to PKC.30. A method for preparing a compound of Formula (I) which comprises:reacting a 3-indol-3-yl-4-phenylfuran-2,5-dione of formula:

where R¹-R⁶ are as defined in claim 1 with ammonia to provide a compoundof Formula (I); or reacting a compound of formula: where R¹-R³ are asdefined in claim 1 and R is alkyl, with a compound of formula:

where R⁴-R⁶ are as defined in claim 1, in the presence of a base; and(iii) optionally converting a compound of Formula (I) to other compoundsof Formula (I); (iv) optionally converting the compound of Formula (I)prepared in Steps (i) or (ii) above, to the corresponding acid additionsalt by treatment with an acid; (v) optionally converting the compoundof Formula (I) prepared in Steps (i) or (ii) above, to the correspondingfree base by treatment with a base; and optionally separating a mixtureof stereoisomers of a compound of Formula (I) prepared in Steps (i) -(v)above, to give a single stereoisomer.